Molecules

2024

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17 pages, 2404 KiB

Open AccessArticle

Plant Extracts and Phytochemicals from the Asteraceae Family with Antiviral Properties

by Jimena Borgo, Mariel S. Wagner, Laura C. Laurella, Orlando G. Elso, Mariana G. Selener, María Clavin, Hernán Bach, César A. N. Catalán, Augusto E. Bivona, Claudia S. Sepúlveda and Valeria P. Sülsen

Molecules 2024, 29(4), 814; https://doi.org/10.3390/molecules29040814 - 9 Feb 2024

Cited by 2 | Viewed by 2684

Abstract

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on [...] Read more.

Asteraceae (Compositae), commonly known as the sunflower family, is one of the largest plant families in the world and includes several species with pharmacological properties. In the search for new antiviral candidates, an in vitro screening against dengue virus (DENV) was performed on a series of dichloromethane and methanolic extracts prepared from six Asteraceae species, including Acmella bellidioides, Campuloclinium macrocephalum, Grindelia pulchella, Grindelia chiloensis, Helenium radiatum, and Viguiera tuberosa, along with pure phytochemicals isolated from Asteraceae: mikanolide (1), eupatoriopicrin (2), eupahakonenin B (3), minimolide (4), estafietin (5), 2-oxo-8-deoxyligustrin (6), santhemoidin C (7), euparin (8), jaceidin (9), nepetin (10), jaceosidin (11), eryodictiol (12), eupatorin (13), and 5-demethylsinensetin (14). Results showed that the dichloromethane extracts of C. macrocephalum and H. radiatum and the methanolic extracts prepared from C. macrocephalum and G. pulchella were highly active and selective against DENV-2, affording EC₅₀ values of 0.11, 0.15, 1.80, and 3.85 µg/mL, respectively, and SIs of 171.0, 18.8, >17.36, and 64.9, respectively. From the pool of phytochemicals tested, compounds 6, 7, and 8 stand out as the most active (EC₅₀ = 3.7, 3.1, and 6.8 µM, respectively; SI = 5.9, 6.7, and >73.4, respectively). These results demonstrate that Asteraceae species and their chemical constituents represent valuable sources of new antiviral molecules. Full article

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2023

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17 pages, 1503 KiB

Open AccessArticle

In Silico and In Vitro Search for Dual Inhibitors of the Trypanosoma brucei and Leishmania major Pteridine Reductase 1 and Dihydrofolate Reductase

by Katharina Possart, Fabian C. Herrmann, Joachim Jose and Thomas J. Schmidt

Molecules 2023, 28(22), 7526; https://doi.org/10.3390/molecules28227526 - 10 Nov 2023

Cited by 3 | Viewed by 1753

Abstract

The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses’ [...] Read more.

The parasites Trypanosoma brucei (Tb) and Leishmania major (Lm) cause the tropical diseases sleeping sickness, nagana, and cutaneous leishmaniasis. Every year, millions of humans, as well as animals, living in tropical to subtropical climates fall victim to these illnesses’ health threats. The parasites’ frequent drug resistance and widely spread natural reservoirs heavily impede disease prevention and treatment. Due to pteridine auxotrophy, trypanosomatid parasites have developed a peculiar enzyme system consisting of dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1) to support cell survival. Extending our previous studies, we conducted a comparative study of the T. brucei (TbDHFR, TbPTR1) and L. major (LmDHFR, LmPTR1) enzymes to identify lead structures with a dual inhibitory effect. A pharmacophore-based in silico screening of three natural product databases (approximately 4880 compounds) was performed to preselect possible inhibitors. Building on the in silico results, the inhibitory potential of promising compounds was verified in vitro against the recombinant DHFR and PTR1 of both parasites using spectrophotometric enzyme assays. Twelve compounds were identified as dual inhibitors against the Tb enzymes (0.2 μM < IC₅₀ < 85.1 μM) and ten against the respective Lm enzymes (0.6 μM < IC₅₀ < 84.5 μM). These highly promising results may represent the starting point for the future development of new leads and drugs utilizing the trypanosomatid pteridine metabolism as a target. Full article

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16 pages, 312 KiB

Open AccessArticle

In Vitro Effect on Plasmodium falciparum and In Vivo Effect on Plasmodium berghei of Annomaal, an Oily Fraction Obtained from the Seeds of Annona squamosa

by Sampada S. Sawant, Satish Y. Gabhe and Kamalinder K. Singh

Molecules 2023, 28(14), 5472; https://doi.org/10.3390/molecules28145472 - 17 Jul 2023

Cited by 2 | Viewed by 1956

Abstract

Malaria remains a life-threatening health problem and is responsible for the high rates of mortality and morbidity in the tropical and subtropical regions of the world. The increasing threat of drug resistance to available artemisinin-based therapy warrants an urgent need to develop new [...] Read more.

Malaria remains a life-threatening health problem and is responsible for the high rates of mortality and morbidity in the tropical and subtropical regions of the world. The increasing threat of drug resistance to available artemisinin-based therapy warrants an urgent need to develop new antimalarial drugs that are safer, more effective, and have a novel mode of action. Natural plants are an excellent source of inspiration in searching for a new antimalarial agent. This research reports a systematic investigation for determining the antimalarial potential of the seeds of A. squamosa. The study shows that the crude seed extract (CSE), protein, saponin, and the oily fractions of the seeds were nontoxic at a 2000 mg/kg body weight dose when tested in Wistar rats, thus revealing high safety is classified as class 5. The oily fraction, Annomaal, demonstrated pronounced antimalarial activity with low IC₅₀ (1.25 ± 0.183 μg/mL) against P. falciparum in vitro. The CSE and Annomaal significantly inhibited the growth of P. berghei parasites in vivo with 58.47% and 61.11% chemo suppression, respectively, while the standard drug artemether showed chemo suppression of 66.75%. Furthermore, the study demonstrated that oral administration of Annomaal at a daily dose of 250 mg/kg/day for 3 days was adequate to provide a complete cure to the P. berghei-infected mice. Annomaal thus holds promise as being patient-compliant due to the shorter treatment schedule, eliminating the need for frequent dosing for extended time periods as required by several synthetic antimalarial drugs. Further studies are needed to determine the active compounds in the oily fraction responsible for antimalarial activity. Full article

7 pages, 1297 KiB

Open AccessCommunication

In Vitro Efficacy of Terpenes from Essential Oils against Sarcoptes scabiei

by Meilin Li, Shenrui Feng, Siyi Huang, Jacques Guillot and Fang Fang

Molecules 2023, 28(8), 3361; https://doi.org/10.3390/molecules28083361 - 11 Apr 2023

Cited by 3 | Viewed by 2422

Abstract

The mite Sarcoptes scabiei is responsible for the emerging or re-emerging skin disease called scabies in humans and sarcoptic mange in animals. Essential oils represent an appealing alternative strategy for the control of Sarcoptes infections, but the commercial development of essential oils may [...] Read more.

The mite Sarcoptes scabiei is responsible for the emerging or re-emerging skin disease called scabies in humans and sarcoptic mange in animals. Essential oils represent an appealing alternative strategy for the control of Sarcoptes infections, but the commercial development of essential oils may be hampered by their inconsistency in efficacy due to their varied chemical compositions. In order to address this issue, we assessed the efficacy of six components (carvacrol, eugenol, geraniol, citral, terpinen-4-ol, and linalool) against S. scabiei. At a concentration of 0.5%, carvacrol presented the best miticidal efficacy, with a median lethal time (LT₅₀) value of 6.7 min, followed by eugenol (56.3 min), geraniol (1.8 h), citral (6.1 h), terpinen-4-ol (22.3 h), and linalool (39.9 h). The LC₅₀ values at 30 min for carvacrol, eugenol, and geraniol were 0.24, 0.79, and 0.91%, respectively. In conclusion, carvacrol, eugenol, and geraniol represent potential complementary or alternative agents for S. scabiei infections in humans or animals. Our study provides a scientific basis for the development of scabicidal products based on essential oils. Full article

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14 pages, 2317 KiB

Open AccessArticle

Lichen-Derived Diffractaic Acid Inhibited Dengue Virus Replication in a Cell-Based System

by Naphat Loeanurit, Truong Lam Tuong, Van-Kieu Nguyen, Vipanee Vibulakhaophan, Kowit Hengphasatporn, Yasuteru Shigeta, Si Xian Ho, Justin Jang Hann Chu, Thanyada Rungrotmongkol, Warinthorn Chavasiri and Siwaporn Boonyasuppayakorn

Molecules 2023, 28(3), 974; https://doi.org/10.3390/molecules28030974 - 18 Jan 2023

Cited by 8 | Viewed by 2609

Abstract

Dengue is a mosquito-borne flavivirus that causes 21,000 deaths annually. Depsides and depsidones of lichens have previously been reported to be antimicrobials. In this study, our objective was to identify lichen-derived depsides and depsidones as dengue virus inhibitors. The 18 depsides and depsidones [...] Read more.

Dengue is a mosquito-borne flavivirus that causes 21,000 deaths annually. Depsides and depsidones of lichens have previously been reported to be antimicrobials. In this study, our objective was to identify lichen-derived depsides and depsidones as dengue virus inhibitors. The 18 depsides and depsidones of Usnea baileyi, Usnea aciculifera, Parmotrema dilatatum, and Parmotrema tsavoense were tested against dengue virus serotype 2. Two depsides and one depsidone inhibited dengue virus serotype 2 without any apparent cytotoxicity. Diffractaic acid, barbatic acid, and Parmosidone C were three active compounds further characterized for their efficacies (EC₅₀), cytotoxicities (CC₅₀), and selectivity index (SI; CC₅₀/EC₅₀). Their EC₅₀ (SI) values were 2.43 ± 0.19 (20.59), 0.91 ± 0.15 (13.33), and 17.42 ± 3.21 (8.95) μM, respectively. Diffractaic acid showed the highest selectivity index, and similar efficacies were also found in dengue serotypes 1–4, Zika, and chikungunya viruses. Cell-based studies revealed that the target was mainly in the late stage with replication and the formation of infectious particles. This report highlights that a lichen-derived diffractaic acid could become a mosquito-borne antiviral lead as its selectivity indices ranged from 8.07 to 20.59 with a proposed target at viral replication. Full article

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2022

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30 pages, 2455 KiB

Open AccessReview

Essential Oils as Novel Anthelmintic Drug Candidates

by Sujogya Kumar Panda, Marijn Daemen, Gunanidhi Sahoo and Walter Luyten

Molecules 2022, 27(23), 8327; https://doi.org/10.3390/molecules27238327 - 29 Nov 2022

Cited by 12 | Viewed by 5242

Abstract

Helminths, with an estimated 1.5 billion annual global infections, are one of the major health challenges worldwide. The current strategy of the World Health Organization to prevent helminth infection includes increasing hygienic awareness, providing better sanitation and preventative anthelmintic drug therapy in vulnerable [...] Read more.

Helminths, with an estimated 1.5 billion annual global infections, are one of the major health challenges worldwide. The current strategy of the World Health Organization to prevent helminth infection includes increasing hygienic awareness, providing better sanitation and preventative anthelmintic drug therapy in vulnerable populations. Nowadays, anthelmintic drugs are used heavily in livestock, both in case of infection and as a preventative measure. However, this has led to the development of resistance against several of the most common drugs, such as levamisole, ivermectin and thiabendazole. As many as 70% of the livestock in developed countries now has helminths that are drug resistant, and multiple resistance is common. Because of this, novel anthelmintics are urgently needed to help combat large-scale production losses. Prior to this review, no comprehensive review of the anthelmintic effects of essential oils and their components existed. Multiple review articles have been published on the uses of a single plant and its extracts that only briefly touch upon their anthelmintic activity. This review aims to provide a detailed overview of essential oils and their components as anthelmintic treatment against a wider variety of helminths. Full article

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13 pages, 5220 KiB

Open AccessArticle

A Composition Analysis and an Antibacterial Activity Mechanism Exploration of Essential Oil Obtained from Artemisia giraldii Pamp

by Guiguo Huo, Xu Li, Mohamed Aamer Abubaker, Tingyu Liang, Ji Zhang and Xuelin Chen

Molecules 2022, 27(21), 7300; https://doi.org/10.3390/molecules27217300 - 27 Oct 2022

Cited by 3 | Viewed by 1853

Abstract

The goal of this work was to use the GC-MS technique to explore the chemical components of Artemisia giraldii Pamp essential oil (AgEo) and to uncover its antibacterial activity, specifically the antibacterial mechanism of this essential oil. There were a total of 63 [...] Read more.

The goal of this work was to use the GC-MS technique to explore the chemical components of Artemisia giraldii Pamp essential oil (AgEo) and to uncover its antibacterial activity, specifically the antibacterial mechanism of this essential oil. There were a total of 63 chemical constituents in the AgEo, monoterpenes (10.2%) and sesquiterpenes (30.14%) were found to be the most common chemical components, with camphor (15.68%) coming in first, followed by germacrene D. (15.29%). AgEo displayed significant reducing power and good scavenging ability on hydroxyl radicals, 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radicals, and 2,2′-Azinobis-(3-ethylbenzthiazoline-6-sulphonate (ABTS) radicals, according to antioxidant data. The diameter of the inhibition zone (DIZ) of AgEo against S. aureus and E. coli was (14.00 ± 1.00) mm and (16.33 ± 1.53) mm, respectively; the minimum inhibitory concentration (MIC) of AgEo against E. coli and S. aureus was 3 μL/mL and 6 μL/mL, respectively; and the minimum bactericidal concentration (MBC) of AgEo against E. coli and S. aureus was 6 μL/mL and 12 μL/mL, respectively. The antibacterial curve revealed that 0.5MIC of AgEo may delay bacterial growth while 2MIC of AgEo could totally suppress bacterial growth. The relative conductivity, alkaline phosphatase (AKP) activity, and protein concentration of the bacterial suspension were all higher after the AgEo treatment than in the control group, and increased as the essential oil concentration was raised. In addition, the cell membrane ruptured and atrophy occurred. The study discovered that AgEo is high in active chemicals and can be used as an antibacterial agent against E. coli and S. aureus, which is critical for AgEo’s future research and development. Full article

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17 pages, 4710 KiB

Open AccessArticle

Structural Basis of Artemisinin Binding Sites in Serum Albumin with the Combined Use of NMR and Docking Calculations

by Alexandra Primikyri, Georgios Papamokos, Themistoklis Venianakis, Marianna Sakka, Vassiliki G. Kontogianni and Ioannis P. Gerothanassis

Molecules 2022, 27(18), 5912; https://doi.org/10.3390/molecules27185912 - 12 Sep 2022

Cited by 6 | Viewed by 2437

Abstract

Artemisinin is known to bind to the main plasma protein carrier serum albumin (SA); however, there are no atomic level structural data regarding its binding mode with serum albumin. Herein, we employed a combined strategy of saturation transfer difference (STD), transfer nuclear Overhauser [...] Read more.

Artemisinin is known to bind to the main plasma protein carrier serum albumin (SA); however, there are no atomic level structural data regarding its binding mode with serum albumin. Herein, we employed a combined strategy of saturation transfer difference (STD), transfer nuclear Overhauser effect spectroscopy (TR-NOESY), STD–total correlation spectroscopy (STD-TOCSY), and Interligand Noes for PHArmacophore Mapping (INPHARMA) NMR methods and molecular docking calculations to investigate the structural basis of the interaction of artemisinin with human and bovine serum albumin (HSA/BSA). A significant number of inter-ligand NOEs between artemisinin and the drugs warfarin and ibuprofen as well as docking calculations were interpreted in terms of competitive binding modes of artemisinin in the warfarin (FA7) and ibuprofen (FA4) binding sites. STD NMR experiments demonstrate that artemisinin is the main analyte for the interaction of the A. annua extract with BSA. The combined strategy of NMR and docking calculations of the present work could be of general interest in the identification of the molecular basis of the interactions of natural products with their receptors even within a complex crude extract. Full article

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19 pages, 3085 KiB

Open AccessArticle

Effect of Bauhinia monandra Kurz Leaf Preparations on Embryonic Stages and Adult Snails of Biomphalaria glabrata (Say, 1818), Schistosoma mansoni Cercariae and Toxicity in Artemia salina

by Thierry Wesley de Albuquerque Aguiar, José Josenildo Batista, Silvio Assis de Oliveira Ferreira, Maíra de Vasconcelos Lima Sampaio, Dewson Rocha Pereira, Magda Rhayanny Assunção Ferreira, Luiz Alberto Lira Soares, Ana Maria Mendonça de Albuquerque Melo, Mônica Camelo Pessoa de Azevedo Albuquerque, André de Lima Aires, Hallysson Douglas Andrade de Araújo and Luana Cassandra Breitenbach Barroso Coelho

Molecules 2022, 27(15), 4993; https://doi.org/10.3390/molecules27154993 - 5 Aug 2022

Cited by 4 | Viewed by 2381

Abstract

Biomphalaria glabrata snails constitute the main vector of schistosomiasis in Brazil, and Bauhinia monandra Kurz, the leaves of which contain BmoLL lectin with biocidal action, is a plant widely found on continents in which the disease is endemic. This work describes the composition [...] Read more.

Biomphalaria glabrata snails constitute the main vector of schistosomiasis in Brazil, and Bauhinia monandra Kurz, the leaves of which contain BmoLL lectin with biocidal action, is a plant widely found on continents in which the disease is endemic. This work describes the composition of B. monandra preparations and the effect on embryos and adult snails, their reproduction parameters and hemocytes. We also describe the results of a comet assay after B. glabrata exposure to sublethal concentrations of the preparations. Additionally, the effects of the preparations on S. mansoni cercariae and environmental monitoring with Artemia salina are described. In the chemical evaluation, cinnamic, flavonoid and saponin derivatives were detected in the two preparations assessed, namely the saline extract and the fraction. Both preparations were toxic to embryos in the blastula, gastrula, trochophore, veliger and hippo stages (LC₅₀ of 0.042 and 0.0478; 0.0417 and 0.0419; 0.0897 and 0.1582; 0.3734 and 0.0974; 0.397 and 0.0970 mg/mL, respectively) and to adult snails (LC₅₀ of 6.6 and 0.87 mg/mL, respectively), which were reproductively affected with decreased egg deposition. In blood cell analysis, characteristic cells for apoptosis, micronucleus and binucleation were detected, while for comet analysis, different degrees of nuclear damage were detected. The fraction was able to cause total mortality of the cercariae and did not present environmental toxicity. Therefore, B. monandra preparations are promising in combating schistosomiasis since they can control both the intermediate host and eliminate the infectious agent, besides being safe to the environment. Full article

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18 pages, 2092 KiB

Open AccessArticle

Assay Development and Identification of the First Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase Inhibitors

by Marie Hoarau, Nattida Suwanakitti, Thaveechai Varatthan, Ratthiya Thiabma, Roonglawan Rattanajak, Netnapa Charoensetakul, Emily K. Redman, Tanatorn Khotavivattana, Tirayut Vilaivan, Yongyuth Yuthavong and Sumalee Kamchonwongpaisan

Molecules 2022, 27(11), 3515; https://doi.org/10.3390/molecules27113515 - 30 May 2022

Cited by 1 | Viewed by 2336

Abstract

In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (PfHPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having [...] Read more.

In the fight towards eradication of malaria, identifying compounds active against new drug targets constitutes a key approach. Plasmodium falciparum 7,8-dihydro-6-hydroxymethylpterin-pyrophosphokinase (PfHPPK) has been advanced as a promising target, as being part of the parasite essential folate biosynthesis pathway while having no orthologue in the human genome. However, no drug discovery efforts have been reported on this enzyme. In this study, we conducted a three-step screening of our in-house antifolate library against PfHPPK using a newly designed PfHPPK-GFP protein construct. Combining virtual screening, differential scanning fluorimetry and enzymatic assay, we identified 14 compounds active against PfHPPK. Compounds’ binding modes were investigated by molecular docking, suggesting competitive binding with the HMDP substrate. Cytotoxicity and in vitro ADME properties of hit compounds were also assessed, showing good metabolic stability and low toxicity. The most active compounds displayed low micromolar IC₅₀ against drug-resistant parasites. The reported hit compounds constitute a good starting point for inhibitor development against PfHPPK, as an alternative approach to tackle the malaria parasite. Full article

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12 pages, 1880 KiB

Open AccessArticle

Isolation and Structural Elucidation of Compounds from Pleiocarpa bicarpellata and Their In Vitro Antiprotozoal Activity

by Ozlem Sevik Kilicaslan, Sylvian Cretton, Luis Quirós-Guerrero, Merveilles A. Bella, Marcel Kaiser, Pascal Mäser, Joseph T. Ndongo and Muriel Cuendet

Molecules 2022, 27(7), 2200; https://doi.org/10.3390/molecules27072200 - 28 Mar 2022

Cited by 4 | Viewed by 2806

Abstract

Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based [...] Read more.

Species of the genus Pleiocarpa are used in traditional medicine against fever and malaria. The present study focuses on the isolation and identification of bioactive compounds from P. bicarpellata extracts, and the evaluation of their antiprotozoal activity. Fractionation and isolation combined to LC-HRMS/MS-based dereplication provided 16 compounds: seven indole alkaloids, four indoline alkaloids, two secoiridoid glycosides, two iridoid glycosides, and one phenolic glucoside. One of the quaternary indole alkaloids (7) and one indoline alkaloid (15) have never been reported before. Their structures were elucidated by analysis of spectroscopic data, including 1D and 2D NMR experiments, UV, IR, and HRESIMS data. The absolute configurations were determined by comparison of the experimental and calculated ECD data. The extracts and isolated compounds were evaluated for their antiprotozoal activity towards Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum, as well as for their cytotoxicity against rat skeletal myoblast L6 cells. The dichloromethane/methanol (1:1) root extract showed strong activity against P. falciparum (IC₅₀ value of 3.5 µg/mL). Among the compounds isolated, tubotaiwine (13) displayed the most significant antiplasmodial activity with an IC₅₀ value of 8.5 µM and a selectivity index of 23.4. Therefore, P. bicarpallata extract can be considered as a source of indole alkaloids with antiplasmodial activity. Full article

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11 pages, 1157 KiB

Open AccessArticle

In Vitro Pharmacological Screening of Essential Oils from Baccharis parvidentata and Lippia origanoides Growing in Brazil

by Wilmer H. Perera, Alexander M. Scherbakov, Galina I. Buravchenko, Ekaterina I. Mikhaevich, Suzana Guimarães Leitão, Paul Cos, Andrey E. Shchekotikhin, Lianet Monzote and William N. Setzer

Molecules 2022, 27(6), 1926; https://doi.org/10.3390/molecules27061926 - 16 Mar 2022

Cited by 6 | Viewed by 2670

Abstract

In this study, the in vitro antimicrobial, antiparasitic, antiproliferative and cytotoxic activities of essential oil from Baccharis parvidentata Malag. (EO-Bp) and Lippia origanoides Kunth (EO-Lo) were explored. The relevant effects were observed against the parasitic protozoans Plasmodium falciparum, Trypanosoma cruzi [...] Read more.

In this study, the in vitro antimicrobial, antiparasitic, antiproliferative and cytotoxic activities of essential oil from Baccharis parvidentata Malag. (EO-Bp) and Lippia origanoides Kunth (EO-Lo) were explored. The relevant effects were observed against the parasitic protozoans Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei and Leishmania amazonensis (ranging 0.6 to 39.7 µg/mL) and malignant MCF-7, MCF-7/HT, 22Rv1, and A431 cell lines (ranging 6.1 to 31.5 µg/mL). In parallel, EO-Bp showed better selective indexes in comparison with EO-Lo against peritoneal macrophages from BALB/c mice and MRC-5 cell line. In conclusion, EO-Lo is known to show a wide range of health benefits that could be added as another potential use of this oil with the current study. In the case of EO-Bp, the wide spectrum of its activities against protozoal parasites and malignant cells, as well as its selectivity in comparison with non-malignant cells, could suggest an interesting candidate for further tests as a new therapeutic alternative. Full article

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15 pages, 2171 KiB

Open AccessArticle

The Antagonizing Role of Heme in the Antimalarial Function of Artemisinin: Elevating Intracellular Free Heme Negatively Impacts Artemisinin Activity in Plasmodium falciparum

by Pan Zhu and Bing Zhou

Molecules 2022, 27(6), 1755; https://doi.org/10.3390/molecules27061755 - 8 Mar 2022

Cited by 8 | Viewed by 2498

Abstract

The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or [...] Read more.

The rich source of heme within malarial parasites has been considered to underly the action specificity of artemisinin. We reasoned that increasing intraparasitic free heme levels might further sensitize the parasites to artemisinin. Various means, such as modulating heme synthesis, degradation, polymerization, or hemoglobin digestion, were tried to boost intracellular heme levels, and under several scenarios, free heme levels were significantly augmented. Interestingly, all results arrived at the same conclusion, i.e., elevating heme acted in a strongly negative way, impacting the antimalarial action of artemisinin, but exerted no effect on several other antimalarial drugs. Suppression of the elevated free heme level by introducing heme oxygenase expression effectively restored artemisinin potency. Consistently, zinc protoporphyrin IX/zinc mesoporphyrin, as analogues of heme, drastically increased free heme levels and, concomitantly, the EC₅₀ values of artemisinin. We were unable to effectively mitigate free heme levels, possibly due to an unknown compensating heme uptake pathway, as evidenced by our observation of efficient uptake of a fluorescent heme homologue by the parasite. Our results thus indicate the existence of an effective and mutually compensating heme homeostasis network in the parasites, including an uncharacterized heme uptake pathway, to maintain a certain level of free heme and that augmentation of the free heme level negatively impacts the antimalarial action of artemisinin. Importance: It is commonly believed that heme is critical in activating the antimalarial action of artemisinins. In this work, we show that elevating free heme levels in the malarial parasites surprisingly negatively impacts the action of artemisinin. We tried to boost free heme levels with various means, such as by modulating heme synthesis, heme polymerization, hemoglobin degradation and using heme analogues. Whenever we saw elevation of free heme levels, reduction in artemisinin potency was also observed. The homeostasis of heme appears to be complex, as there exists an unidentified heme uptake pathway in the parasites, nullifying our attempts to effectively reduce intraparasitic free heme levels. Our results thus indicate that too much heme is not good for the antimalarial action of artemisinins. This research can help us better understand the biological properties of this mysterious drug. Full article

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2021

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17 pages, 2676 KiB

Open AccessArticle

Discovery of Novel Cyclic Ethers with Synergistic Antiplasmodial Activity in Combination with Valinomycin

by Daniel J. Watson, Paul R. Meyers, Kojo Sekyi Acquah, Godwin A. Dziwornu, Christopher Bevan Barnett and Lubbe Wiesner

Molecules 2021, 26(24), 7494; https://doi.org/10.3390/molecules26247494 - 10 Dec 2021

Cited by 4 | Viewed by 2452

Abstract

With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided [...] Read more.

With drug resistance threatening our first line antimalarial treatments, novel chemotherapeutics need to be developed. Ionophores have garnered interest as novel antimalarials due to their theorized ability to target unique systems found in the Plasmodium-infected erythrocyte. In this study, during the bioassay-guided fractionation of the crude extract of Streptomyces strain PR3, a group of cyclodepsipeptides, including valinomycin, and a novel class of cyclic ethers were identified and elucidated. Further study revealed that the ethers were cyclic polypropylene glycol (cPPG) oligomers that had leached into the bacterial culture from an extraction resin. Molecular dynamics analysis suggests that these ethers are able to bind cations such as K⁺, NH₄⁺ and Na⁺. Combination studies using the fixed ratio isobologram method revealed that the cPPGs synergistically improved the antiplasmodial activity of valinomycin and reduced its cytotoxicity in vitro. The IC₅₀ of valinomycin against P. falciparum NF54 improved by 4–5-fold when valinomycin was combined with the cPPGs. Precisely, it was improved from 3.75 ± 0.77 ng/mL to 0.90 ± 0.2 ng/mL and 0.75 ± 0.08 ng/mL when dosed in the fixed ratios of 3:2 and 2:3 of valinomycin to cPPGs, respectively. Each fixed ratio combination displayed cytotoxicity (IC₅₀) against the Chinese Hamster Ovary cell line of 57–65 µg/mL, which was lower than that of valinomycin (12.4 µg/mL). These results indicate that combinations with these novel ethers may be useful in repurposing valinomycin into a suitable and effective antimalarial. Full article

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12 pages, 825 KiB

Open AccessArticle

Dianthiamides A–E, Proline-Containing Orbitides from Dianthus chinensis

by Jin Woo Lee, Jun Gu Kim, Jae Sang Han, Yong Beom Cho, Yu Jin Lee, Dongho Lee, Dae Hwan Shin, Jin Tae Hong, Mi Kyeong Lee and Bang Yeon Hwang

Molecules 2021, 26(23), 7275; https://doi.org/10.3390/molecules26237275 - 30 Nov 2021

Cited by 2 | Viewed by 1911

Abstract

Orbitides are plant-derived small cyclic peptides with a wide range of biological activities. Phytochemical investigation of the whole plants of Dianthus chinensis was performed with the aim to discover new bioactive orbitides. Five undescribed proline-containing orbitides, dianthiamides A–E (1–5), [...] Read more.

Orbitides are plant-derived small cyclic peptides with a wide range of biological activities. Phytochemical investigation of the whole plants of Dianthus chinensis was performed with the aim to discover new bioactive orbitides. Five undescribed proline-containing orbitides, dianthiamides A–E (1–5), were isolated from a methanolic extract of Dianthus chinensis. Their structures were elucidated by extensive analysis of 1D and 2D NMR and HRESI–TOF–MS as well as ESI–MS/MS fragmentation data. The absolute configuration of the amino acid residues of compounds 1–5 was determined by Marfey’s method. All compounds were tested for their cytotoxic activity, and dianthiamide A (1) exhibited weak activity against A549 cell line with IC₅₀ value of 47.9 μM. Full article

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14 pages, 2532 KiB

Open AccessArticle

Alkyne-Tagged Apigenin, a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads

by Kowit Hengphasatporn, Benyapa Kaewmalai, Somruedee Jansongsaeng, Vishnu Nayak Badavath, Thanaphon Saelee, Thamonwan Chokmahasarn, Tanatorn Khotavivattana, Yasuteru Shigeta, Thanyada Rungrotmongkol and Siwaporn Boonyasuppayakorn

Molecules 2021, 26(22), 6967; https://doi.org/10.3390/molecules26226967 - 18 Nov 2021

Cited by 8 | Viewed by 3439

Abstract

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne [...] Read more.

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC₅₀ of 2.36 ± 0.22, and 10.55 ± 3.37 µM, respectively, while the cytotoxicities were similar to the original apigenin at the CC₅₀ of 70.34 ± 11.79, and 82.82 ± 11.68 µM, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface. Full article

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10 pages, 1651 KiB

Open AccessArticle

Quantitative Structure–Activity Relationships of Natural-Product-Inspired, Aminoalkyl-Substituted 1-Benzopyrans as Novel Antiplasmodial Agents

by Friederike M. Wunsch, Bernhard Wünsch, Freddy A. Bernal and Thomas J. Schmidt

Molecules 2021, 26(17), 5249; https://doi.org/10.3390/molecules26175249 - 30 Aug 2021

Cited by 4 | Viewed by 2177

Abstract

On the basis of the finding that various aminoalkyl-substituted chromene and chromane derivatives possess strong and highly selective in vitro bioactivity against Plasmodium falciparum, the pathogen responsible for tropical malaria, we performed a structure–activity relationship study for such compounds. With structures and [...] Read more.

On the basis of the finding that various aminoalkyl-substituted chromene and chromane derivatives possess strong and highly selective in vitro bioactivity against Plasmodium falciparum, the pathogen responsible for tropical malaria, we performed a structure–activity relationship study for such compounds. With structures and activity data of 52 congeneric compounds from our recent studies, we performed a three-dimensional quantitative structure–activity relationship (3D-QSAR) study using the comparative molecular field analysis (CoMFA) approach as implemented in the Open3DQSAR software. The resulting model displayed excellent internal and good external predictive power as well as good robustness. Besides insights into the molecular interactions and structural features influencing the antiplasmodial activity, this model now provides the possibility to predict the activity of further untested compounds to guide our further synthetic efforts to develop even more potent antiplasmodial chromenes/chromanes. Full article

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17 pages, 3709 KiB

Open AccessArticle

Discovery of New Hits as Antitrypanosomal Agents by In Silico and In Vitro Assays Using Neolignan-Inspired Natural Products from Nectandra leucantha

by Sheila C. Araujo, Fernanda S. Sousa, Thais A. Costa-Silva, Andre G. Tempone, João Henrique G. Lago and Kathia M. Honorio

Molecules 2021, 26(14), 4116; https://doi.org/10.3390/molecules26144116 - 6 Jul 2021

Cited by 1 | Viewed by 2434

Abstract

In the present study, the phytochemical study of the n-hexane extract from flowers of Nectandra leucantha (Lauraceae) afforded six known neolignans (1–6) as well as one new metabolite (7), which were characterized by analysis of NMR, [...] Read more.

In the present study, the phytochemical study of the n-hexane extract from flowers of Nectandra leucantha (Lauraceae) afforded six known neolignans (1–6) as well as one new metabolite (7), which were characterized by analysis of NMR, IR, UV, and ESI-HRMS data. The new compound 7 exhibited potent activity against the clinically relevant intracellular forms of T. cruzi (amastigotes), with an IC₅₀ value of 4.3 μM and no observed mammalian cytotoxicity in fibroblasts (CC₅₀ > 200 μM). Based on the results obtained and our previous antitrypanosomal data of 50 natural and semi-synthetic related neolignans, 2D and 3D molecular modeling techniques were employed to help the design of new neolignan-based compounds with higher activity. The results obtained from the models were important to understand the main structural features related to the biological response of the neolignans and to aid in the design of new neolignan-based compounds with better biological activity. Therefore, the results acquired from phytochemical, biological, and in silico studies showed that the integration of experimental and computational techniques consists of a powerful tool for the discovery of new prototypes for development of new drugs to treat CD. Full article

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8 pages, 1383 KiB

Open AccessArticle

Antiplasmodial and Cytotoxic Flavonoids from Pappea capensis (Eckl. & Zeyh.) Leaves

by Nasir Tajuddeen, Tarryn Swart, Heinrich C. Hoppe and Fanie R. van Heerden

Molecules 2021, 26(13), 3875; https://doi.org/10.3390/molecules26133875 - 25 Jun 2021

Cited by 11 | Viewed by 2643

Abstract

Ethnobotanical surveys indicate that the Masai and Kikuyu in Kenya, the Venda in South Africa, and the Gumuz people of Ethiopia use Pappea capensis for the treatment of malaria. The present study aimed to investigate the phytochemical and antiplasmodial properties of the plant [...] Read more.

Ethnobotanical surveys indicate that the Masai and Kikuyu in Kenya, the Venda in South Africa, and the Gumuz people of Ethiopia use Pappea capensis for the treatment of malaria. The present study aimed to investigate the phytochemical and antiplasmodial properties of the plant leaves. The bioactive compounds were isolated using chromatographic techniques. The structures were established using NMR, HRMS, and UV spectroscopy. Antiplasmodial activity of P. capensis leaf extract and isolated compounds against chloroquine-sensitive 3D7 P. falciparum was evaluated using the parasite lactate dehydrogenase assay. Cytotoxicity against HeLa (human cervix adenocarcinoma) cells was determined using the resazurin assay. The extract inhibited the viability of Plasmodium falciparum by more than 80% at 50 µg/mL, but it was also cytotoxic against HeLa cells at the same concentration. Chromatographic purification of the extract led to the isolation of four flavonoid glycosides and epicatechin. The compounds displayed a similar activity pattern with the extract against P. falciparum and HeLa cells. The results from this study suggest that the widespread use of P. capensis in traditional medicine for the treatment of malaria might have some merits. However, more selectivity studies are needed to determine whether the leaf extract is cytotoxic against noncancerous cells. Full article

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6 pages, 455 KiB

Open AccessArticle

Boswellic Acids Show In Vitro Activity against Leishmania donovani

by Hippolyt L. Greve, Marcel Kaiser, Pascal Mäser and Thomas J. Schmidt

Molecules 2021, 26(12), 3651; https://doi.org/10.3390/molecules26123651 - 15 Jun 2021

Cited by 7 | Viewed by 2124

Abstract

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from Boswellia serrata resin. 11-keto-β-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against [...] Read more.

In continuation of our search for leads from medicinal plants against protozoal pathogens, we detected antileishmanial activity in polar fractions of a dichloromethane extract from Boswellia serrata resin. 11-keto-β-boswellic acid (KBA) could be isolated from these fractions and was tested in vitro against Leishmania donovani axenic amastigotes along with five further boswellic acid derivatives. 3-O-acetyl-11-keto-β-boswellic acid (AKBA) showed the strongest activity with an IC₅₀ value of 0.88 µM against axenic amastigotes but was inactive against intracellular amastigotes in murine macrophages Full article

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11 pages, 930 KiB

Open AccessArticle

Salvia officinalis L.: Antitrypanosomal Activity and Active Constituents against Trypanosoma brucei rhodesiense

by Núria Llurba Montesino, Marcel Kaiser, Pascal Mäser and Thomas J. Schmidt

Molecules 2021, 26(11), 3226; https://doi.org/10.3390/molecules26113226 - 27 May 2021

Cited by 4 | Viewed by 2427

Abstract

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. [...] Read more.

As part of our studies on antiprotozoal activity of approved herbal medicinal products, we previously found that a commercial tincture from Salvia officinalis L. (common Sage, Lamiaceae) possesses high activity against Trypanosoma brucei rhodesiense (Tbr), causative agent of East African Human Trypanosomiasis. We have now investigated in detail the antitrypanosomal constituents of this preparation. A variety of fractions were tested for antitrypanosomal activity and analyzed by UHPLC/+ESI QqTOF MS. The resulting data were used to generate a partial least squares (PLS) regression model that highlighted eight particular constituents that were likely to account for the major part of the bioactivity. These compounds were then purified and identified and their activity against the pathogen tested. All identified compounds (one flavonoid and eight diterpenes) displayed significant activity against Tbr, in some cases higher than that of the total tincture. From the overall results, it can be concluded that the antitrypanosomal activity of S. officinalis L. is, for the major part, caused by abietane-type diterpenes of the rosmanol/rosmaquinone group. Full article

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23 pages, 2147 KiB

Open AccessArticle

Identification of Kaurane-Type Diterpenes as Inhibitors of Leishmania Pteridine Reductase I

by Chonny Herrera-Acevedo, Areli Flores-Gaspar, Luciana Scotti, Francisco Jaime Bezerra Mendonça-Junior, Marcus Tullius Scotti and Ericsson Coy-Barrera

Molecules 2021, 26(11), 3076; https://doi.org/10.3390/molecules26113076 - 21 May 2021

Cited by 13 | Viewed by 3713

Abstract

The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, [...] Read more.

The current treatments against Leishmania parasites present high toxicity and multiple side effects, which makes the control and elimination of leishmaniasis challenging. Natural products constitute an interesting and diverse chemical space for the identification of new antileishmanial drugs. To identify new drug options, an in-house database of 360 kauranes (tetracyclic diterpenes) was generated, and a combined ligand- and structure-based virtual screening (VS) approach was performed to select potential inhibitors of Leishmania major (Lm) pteridine reductase I (PTR1). The best-ranked kauranes were employed to verify the validity of the VS approach through LmPTR1 enzyme inhibition assay. The half-maximal inhibitory concentration (IC₅₀) values of selected bioactive compounds were examined using the random forest (RF) model (i.e., 2β-hydroxy-menth-6-en-5β-yl ent-kaurenoate (135) and 3α-cinnamoyloxy-ent-kaur-16-en-19-oic acid (302)) were below 10 μM. A compound similar to 302, 3α-p-coumaroyloxy-ent-kaur-16-en-19-oic acid (302a), was also synthesized and showed the highest activity against LmPTR1. Finally, molecular docking calculations and molecular dynamics simulations were performed for the VS-selected, most-active kauranes within the active sites of PTR1 hybrid models, generated from three Leishmania species that are known to cause cutaneous leishmaniasis in the new world (i.e., L. braziliensis, L. panamensis, and L. amazonensis) to explore the targeting potential of these kauranes to other species-dependent variants of this enzyme. Full article

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15 pages, 5013 KiB

Open AccessArticle

Nopol-Based Quinoline Derivatives as Antiplasmodial Agents

by Rogers J. Nyamwihura, Huaisheng Zhang, Jasmine T. Collins, Olamide Crown and Ifedayo Victor Ogungbe

Molecules 2021, 26(4), 1008; https://doi.org/10.3390/molecules26041008 - 14 Feb 2021

Cited by 10 | Viewed by 2735

Abstract

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new [...] Read more.

Malaria remains a significant cause of morbidity and mortality in Sub-Saharan Africa and South Asia. While clinical antimalarials are efficacious when administered according to local guidelines, resistance to every class of antimalarials is a persistent problem. There is a constant need for new antimalarial therapeutics that complement parasite control strategies to combat malaria, especially in the tropics. In this work, nopol-based quinoline derivatives were investigated for their inhibitory activity against Plasmodium falciparum, one of the parasites that cause malaria. The nopyl-quinolin-8-yl amides (2–4) were moderately active against the asexual blood stage of chloroquine-sensitive strain Pf3D7 but inactive against chloroquine-resistant strains PfK1 and PfNF54. The nopyl-quinolin-4-yl amides and nopyl-quinolin-4-yl-acetates analogs were generally less active on all three strains. Interesting, the presence of a chloro substituent at C7 of the quinoline ring of amide 8 resulted in sub-micromolar EC₅₀ in the PfK1 strain. However, 8 was more than two orders of magnitude less active against Pf3D7 and PfNF54. Overall, the nopyl-quinolin-8-yl amides appear to share similar antimalarial profile (asexual blood-stage) with previously reported 8-aminoquinolines like primaquine. Future work will focus on investigating the moderately active and selective nopyl-quinolin-8-yl amides on the gametocyte or liver stages of Plasmodium falciparum and Plasmodium vivax. Full article

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20 pages, 2652 KiB

Open AccessArticle

The Alkaloid-Enriched Fraction of Pachysandra terminalis (Buxaceae) Shows Prominent Activity against Trypanosoma brucei rhodesiense

by Dagmar Flittner, Marcel Kaiser, Pascal Mäser, Norberto P. Lopes and Thomas J. Schmidt

Molecules 2021, 26(3), 591; https://doi.org/10.3390/molecules26030591 - 23 Jan 2021

Cited by 7 | Viewed by 2363

Abstract

In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from Holarrhena africana A. DC. (Apocynaceae) and Buxus sempervirens L. (Buxaceae), respectively, are strong and selective antitrypanosomal agents, we have extended these [...] Read more.

In the course of our studies on antiprotozoal natural products and following our recent discovery that certain aminosteroids and aminocycloartanoid compounds from Holarrhena africana A. DC. (Apocynaceae) and Buxus sempervirens L. (Buxaceae), respectively, are strong and selective antitrypanosomal agents, we have extended these studies to another plant, related to the latter—namely, Pachysandra terminalis Sieb. and Zucc. (Buxaceae). This species is known to contain aminosteroids similar to those of Holarrhena and structurally related to the aminocycloartanoids of Buxus. The dicholoromethane extract obtained from aerial parts of P. terminalis and, in particular, its alkaloid fraction obtained by acid–base partitioning showed prominent activity against Trypanosoma brucei rhodesiense (Tbr). Activity-guided fractionation along with extended UHPLC-(+)ESI QTOF MS analyses coupled with partial least squares (PLS) regression modelling relating the analytical profiles of various fractions with their bioactivity against Tbr highlighted eighteen constituents likely responsible for the antitrypanosomal activity. Detailed analysis of their (+)ESI mass spectral fragmentation allowed identification of four known constituents of P. terminalis as well as structural characterization of ten further amino-/amidosteroids not previously reported from this plant. Full article

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1 pages, 154 KiB

Open AccessEditorial

Special Issue “Artemisinin (Qinghaosu): Commemorative Issue in Honor of Professor Youyou Tu on the Occasion of Her 80th Anniversary” in International Molecules Published in 2010

by Yan He and Shu-Kun Lin

Molecules 2021, 26(2), 279; https://doi.org/10.3390/molecules26020279 - 8 Jan 2021

Cited by 1 | Viewed by 2081

Abstract

It has been more than 10 years since we published the Special Issue “Artemisinin (Qinghaosu): commemorative issue in honor of Professor Youyou Tu on the occasion of her 80th anniversary” (Abbreviated as “the Artemisinins Special Issue”) [...] Full article

2020

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10 pages, 1118 KiB

Open AccessArticle

Target-Guided Isolation of O-tigloylcyclovirobuxeine-B from Buxus sempervirens L. by Centrifugal Partition Chromatography

by Lara U. Szabó and Thomas J. Schmidt

Molecules 2020, 25(20), 4804; https://doi.org/10.3390/molecules25204804 - 19 Oct 2020

Cited by 7 | Viewed by 2424

Abstract

The increasing drug resistance of malaria parasites challenges the treatment of this life-threatening disease. Consequently, the development of innovative and effective antimalarial drugs is inevitable. O-tigloylcyclovirobuxeine-B, a nor-cycloartane alkaloid from Buxussempervirens L., has shown promising and selective in vitro activity [...] Read more.

The increasing drug resistance of malaria parasites challenges the treatment of this life-threatening disease. Consequently, the development of innovative and effective antimalarial drugs is inevitable. O-tigloylcyclovirobuxeine-B, a nor-cycloartane alkaloid from Buxussempervirens L., has shown promising and selective in vitro activity in previous studies against Plasmodiumfalciparum (Pf), causative agent of Malaria tropica. For further investigations, it is indispensable to develop an advanced and efficient isolation procedure of this valuable natural product. Accordingly, we used liquid–liquid chromatography including centrifugal partition chromatography (CPC) to obtain the pure alkaloid on a semi-preparative scale. Identification and characterization of the target compound was accomplished by UHPLC/+ESI-QqTOF-MS/MS, ¹H NMR and ¹³C NMR. In conclusion, this work provides a new and efficient method to obtain O-tigloylcyclovirobuxeine-B, a valuable natural product, as a promising antiplasmodial lead structure for the development of innovative and safe medicinal agents. Full article

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12 pages, 1590 KiB

Open AccessArticle

Trypanocidal Activity of Four Sesquiterpene Lactones Isolated from Asteraceae Species

by Orlando G. Elso, Augusto E. Bivona, Andrés Sanchez Alberti, Natacha Cerny, Lucas Fabian, Celina Morales, César A. N. Catalán, Emilio L. Malchiodi, Silvia I. Cazorla and Valeria P. Sülsen

Molecules 2020, 25(9), 2014; https://doi.org/10.3390/molecules25092014 - 25 Apr 2020

Cited by 23 | Viewed by 3635

Abstract

The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide have been isolated from Argentinean Astearaceae species and have been found to be active against Trypanosoma cruzi epimastigotes. The aim of this work was to evaluate the activity of these compounds by analyzing their [...] Read more.

The sesquiterpene lactones eupatoriopicrin, estafietin, eupahakonenin B and minimolide have been isolated from Argentinean Astearaceae species and have been found to be active against Trypanosoma cruzi epimastigotes. The aim of this work was to evaluate the activity of these compounds by analyzing their effect against the stages of the parasites that are infective for the human. Even more interesting, we aimed to determine the effect of the most active and selective compound on an in vivo model of T. cruzi infection. Eupatoriopicrin was the most active against amastigotes and tripomastigotes (IC₅₀ = 2.3 µg/mL, and 7.2 µg/mL, respectively) and displayed a high selectivity index. This compound was selected to study on an in vivo model of T. cruzi infection. The administration of 1 mg/kg/day of eupatoriopicrin for five consecutive days to infected mice produced a significant reduction in the parasitaemia levels in comparison with non-treated animals (area under parasitaemia curves 4.48 vs. 30.47, respectively). Skeletal muscular tissues from eupatopicrin-treated mice displayed only focal and interstitial lymphocyte inflammatory infiltrates and small areas of necrotic; by contrast, skeletal tissues from T. cruzi infected mice treated with the vehicle showed severe lymphocyte inflammatory infiltrates with necrosis of the adjacent myocytes. The results indicate that eupatoriopicrin could be considered a promising candidate for the development of new therapeutic agents for Chagas disease. Full article

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2019

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16 pages, 479 KiB

Open AccessArticle

Antiprotozoal Activity of Turkish Origanum onites Essential Oil and Its Components

by Deniz Tasdemir, Marcel Kaiser, Betül Demirci, Fatih Demirci and K. Hüsnü Can Baser

Molecules 2019, 24(23), 4421; https://doi.org/10.3390/molecules24234421 - 3 Dec 2019

Cited by 43 | Viewed by 7399

Abstract

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of [...] Read more.

Essential oil of Origanum species is well known for antimicrobial activity, but only a few have been evaluated in narrow spectrum antiprotozoal assays. Herein, we assessed the antiprotozoal potential of Turkish Origanum onites L. oil and its major constituents against a panel of parasitic protozoa. The essential oil was obtained by hydrodistillation from the dried herbal parts of O. onites and analyzed by Gas Chromatography-Flame Ionization Detector (GC-FID) and Gas Chromatography coupled with Mass Spectrometry (GC-MS). The in vitro activity of the oil and its major components were evaluated against Trypanosoma brucei rhodesiense, T. cruzi, Leishmania donovani, and Plasmodium falciparum. The main component of the oil was identified as carvacrol (70.6%), followed by linalool (9.7%), p-cymene (7%), γ-terpinene (2.1%), and thymol (1.8%). The oil showed significant in vitro activity against T. b. rhodesiense (IC₅₀ 180 ng/mL), and moderate antileishmanial and antiplasmodial effects, without toxicity to mammalian cells. Carvacrol, thymol, and 10 additional abundant oil constituents were tested against the same panel; carvacrol and thymol retained the oil’s in vitro antiparasitic potency. In the T. b. brucei mouse model, thymol, but not carvacrol, extended the mean survival of animals. This study indicates the potential of the essential oil of O. onites and its constituents in the treatment of protozoal infections. Full article

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13 pages, 2010 KiB

Open AccessArticle

Chemical Constituents of Anacardium occidentale as Inhibitors of Trypanosoma cruzi Sirtuins

by Tanira Matutino Bastos, Helena Mannochio Russo, Nilmar Silvio Moretti, Sergio Schenkman, Laurence Marcourt, Mahabir Prashad Gupta, Jean-Luc Wolfender, Emerson Ferreira Queiroz and Milena Botelho Pereira Soares

Molecules 2019, 24(7), 1299; https://doi.org/10.3390/molecules24071299 - 3 Apr 2019

Cited by 22 | Viewed by 5436

Abstract

Benznidazole and nifurtimox, the only drugs available for the treatment of Chagas disease, have limited efficacy and have been associated with severe adverse side effects. Thus, there is an urgent need to find new biotargets for the identification of novel bioactive compounds against [...] Read more.

Benznidazole and nifurtimox, the only drugs available for the treatment of Chagas disease, have limited efficacy and have been associated with severe adverse side effects. Thus, there is an urgent need to find new biotargets for the identification of novel bioactive compounds against the parasite and with low toxicity. Silent information regulator 2 (Sir2) enzymes, or sirtuins, have emerged as attractive targets for the development of novel antitrypanosomatid agents. In the present work, we evaluated the inhibitory effect of natural compounds isolated from cashew nut (Anacardium occidentale, L. Anacardiaceae) against the target enzymes TcSir2rp1 and TcSir2rp3 as well as the parasite. Two derivates of cardol (1, 2), cardanol (3, 4), and anacardic acid (5, 6) were investigated. The two anacardic acids (5, 6) inhibited both TcSir2rp1 and TcSir2rp3, while the cardol compound (2) inhibited only TcSir2rp1. The most potent sirtuin inhibitor active against the parasite was the cardol compound (2), with an EC₅₀ value of 12.25 µM, similar to that of benznidazole. Additionally, compounds (1, 4), which were inactive against the sirtuin targets, presented anti-T. cruzi effects. In conclusion, our results showed the potential of Anacardium occidentale compounds for the development of potential sirtuin inhibitors and anti-Trypanosoma cruzi agents. Full article

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8 pages, 718 KiB

Open AccessArticle

Antitrypanosomal Activity of Sesquiterpene Lactones from Helianthus tuberosus L. Including a New Furanoheliangolide with an Unusual Structure

by Anna Galkina, Nico Krause, Mairin Lenz, Constantin G. Daniliuc, Marcel Kaiser and Thomas J. Schmidt

Molecules 2019, 24(6), 1068; https://doi.org/10.3390/molecules24061068 - 18 Mar 2019

Cited by 7 | Viewed by 4387

Abstract

As part of our efforts to exploit the antitrypanosomal potential of sesquiterpene lactones (STL) from Helianthus tuberosus L. (Asteraceae), besides the known 4,15-iso-atriplicolide tiglate, -methacrylate and -isobutyrate, a hitherto unknown STL was isolated. Its structure was solved by extensive NMR measurements [...] Read more.

As part of our efforts to exploit the antitrypanosomal potential of sesquiterpene lactones (STL) from Helianthus tuberosus L. (Asteraceae), besides the known 4,15-iso-atriplicolide tiglate, -methacrylate and -isobutyrate, a hitherto unknown STL was isolated. Its structure was solved by extensive NMR measurements and confirmed by single crystal X-ray crystallography. This novel compound is a structural analog 4,15-iso-atriplicolide tiglate that possesses the same basic furanoheliangolide skeleton but differs in the position of the oxo function which is at C-2 instead of C-1, as well as in the fact that the oxygen atom of the furanoid ring is part of a hemiketal structure at C-3 and a double bond between C-5 and C-6. For this new STL we propose the name heliantuberolide-8-O-tiglate. Its activity against Trypanosoma brucei rhodesiense (causative agent of East African Human Typanosomiasis, Trypanosoma cruzi (Chagas Disease), Leishmania donovani (Visceral Leishmaniasis) and Plasmodium falciparum (Tropical Malaria) as well as cytotoxicity against rat skeletal myoblasts (L6 cell line) was determined along with those of the hitherto untested 4,15-iso-atriplicolide methacrylate and isobutyrate. In comparison with the iso-atriplicolide esters, the new compound showed a much lower level of bioactivity. Full article

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2018

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13 pages, 3290 KiB

Open AccessArticle

Antileishmanial Activity of Dimeric Flavonoids Isolated from Arrabidaea brachypoda

by Vinícius P. C. Rocha, Cláudia Quintino da Rocha, Emerson Ferreira Queiroz, Laurence Marcourt, Wagner Vilegas, Gabriela B. Grimaldi, Pascal Furrer, Éric Allémann, Jean-Luc Wolfender and Milena B. P. Soares

Molecules 2019, 24(1), 1; https://doi.org/10.3390/molecules24010001 - 20 Dec 2018

Cited by 30 | Viewed by 5609

Abstract

Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs [...] Read more.

Leishmaniasis are diseases caused by parasites belonging to Leishmania genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from Arrabidaea brachypoda. Three compounds were tested against Leishmana sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of L. amazonensis, without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in L. amazonensis-infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against Leishmania. Full article

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19 pages, 1559 KiB

Open AccessArticle

Solvent Extraction and Identification of Active Anticariogenic Metabolites in Piper cubeba L. through ¹H-NMR-Based Metabolomics Approach

by Raja Nur Asila Raja Mazlan, Yaya Rukayadi, M. Maulidiani and Intan Safinar Ismail

Molecules 2018, 23(7), 1730; https://doi.org/10.3390/molecules23071730 - 16 Jul 2018

Cited by 9 | Viewed by 5156

Abstract

The aim of this study was to determine the effects of different solvents for extraction, liquid–liquid partition, and concentrations of extracts and fractions of Piper cubeba L. on anticariogenic; antibacterial and anti-inflammatory activity against oral bacteria. Furthermore, ¹H-Nuclear Magnetic Resonance (NMR) coupled [...] Read more.

The aim of this study was to determine the effects of different solvents for extraction, liquid–liquid partition, and concentrations of extracts and fractions of Piper cubeba L. on anticariogenic; antibacterial and anti-inflammatory activity against oral bacteria. Furthermore, ¹H-Nuclear Magnetic Resonance (NMR) coupled with multivariate data analysis (MVDA) was applied to discriminate between the extracts and fractions and examine the metabolites that correlate to the bioactivities. All tested bacteria were susceptible to Piper cubeba L. extracts and fractions. Different solvents extraction, liquid–liquid partition and concentrations of extracts and fractions have partially influenced the antibacterial activity. MTT assay showed that P. cubeba L. extracts and fractions were not toxic to RAW 264.7 cells at selected concentrations. Anti-inflammatory activity evaluated by nitric oxide (NO) production in lipopolysaccharide (LPS) stimulated cells showed a reduction in NO production in cells treated with P. cubeba L. extracts and fractions, compared to those without treatment. Twelve putative metabolites have been identified, which are (1) cubebin, (2) yatein, (3) hinokinin, (4) dihydrocubebin, (5) dihydroclusin, (6) cubebinin, (7) magnosalin, (8) p-cymene, (9) piperidine, (10) cubebol, (11) d-germacrene and (12) ledol. Different extraction and liquid–liquid partition solvents caused separation in principal component analysis (PCA) models. The partial least squares (PLS) models showed that higher anticariogenic activity was related more to the polar solvents, despite some of the active metabolites also present in the non-polar solvents. Hence, P. cubeba L. extracts and fractions exhibited antibacterial and anti-inflammatory activity and have potential to be developed as the anticariogenic agent. Full article

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12 pages, 4724 KiB

Open AccessArticle

A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis

by Charles Okeke Nnadi, Julia Barbara Althaus, Ngozi Justina Nwodo and Thomas Jürgen Schmidt

Molecules 2018, 23(5), 1113; https://doi.org/10.3390/molecules23051113 - 8 May 2018

Cited by 17 | Viewed by 5678

Abstract

As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are [...] Read more.

As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr), with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R², Q², and P² for partial least squares (PLS) regression, internal cross-validation (leave-one-out), and external predictions (test set), respectively, as well as the corresponding standard deviation error in prediction (SDEP) and F-values). With R² = 0.99, Q² = 0.83 and P² = 0.79 for anti-Tbr activity and R² = 0.94, Q² = 0.64, P² = 0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common structure–activity relationship (SAR) and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization. Full article

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8 pages, 621 KiB

Open AccessFeature PaperCommunication

Bauerenol Acetate, the Pentacyclic Triterpenoid from Tabernaemontana longipes, is an Antitrypanosomal Agent

by Simira Carothers, Rogers Nyamwihura, Jasmine Collins, Huaisheng Zhang, HaJeung Park, William N. Setzer and Ifedayo Victor Ogungbe

Molecules 2018, 23(2), 355; https://doi.org/10.3390/molecules23020355 - 8 Feb 2018

Cited by 8 | Viewed by 4772

Abstract

The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory [...] Read more.

The Latin American plant Tabernaemontana longipes was studied in this work as a potential source of antiparasitic agents. The chloroform extract of T. longipes leaves was separated into several fractions, and tested for antitrypanosomal activity. One of the fractions displayed significant growth inhibitory activity against Trypanosoma brucei. The active principle in the fraction was isolated, purified, and characterized by NMR and mass spectrometry. The antitrypanosomal agent in the CHCl₃ extract of T. longipes leaves is the pentacyclic triterpenoid bauerenol acetate. A metabolite profiling assay suggest that the triterpenoid influences cholesterol metabolism. The molecular target(s) of bauerenol and its acetate, like many other antiparasitic pentacyclic triterpenoids is/are unknown, but they present privileged structural scaffolds that can be explored for structure-based activity optimization studies using phenotypic assays. Full article

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8 pages, 541 KiB

Open AccessArticle

Sesquiterpene Lactones from Vernonia cinerascens Sch. Bip. and Their in Vitro Antitrypanosomal Activity

by Njogu M. Kimani, Josphat C. Matasyoh, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2018, 23(2), 248; https://doi.org/10.3390/molecules23020248 - 27 Jan 2018

Cited by 21 | Viewed by 4753

Abstract

In the endeavor to obtain new antitrypanosomal agents, particularly sesquiterpene lactones, from Kenyan plants of the family Asteraceae, Vernonia cinerascens Sch. Bip. was investigated. Bioactivity-guided fractionation and isolation in conjunction with LC/MS-based dereplication has led to the identification of vernodalol (1) [...] Read more.

In the endeavor to obtain new antitrypanosomal agents, particularly sesquiterpene lactones, from Kenyan plants of the family Asteraceae, Vernonia cinerascens Sch. Bip. was investigated. Bioactivity-guided fractionation and isolation in conjunction with LC/MS-based dereplication has led to the identification of vernodalol (1) and isolation of vernodalin (2), 11β,13-dihydrovernodalin (3), 11β,13-dihydrovernolide (4), vernolide (5), 11β,13-dihydrohydroxyvernolide (6), hydroxyvernolide (7), and a new germacrolide type sesquiterpene lactone vernocinerascolide (8) from the dichloromethane extract of V. cinerascens leaves. Compounds 3–8 were characterized by extensive analysis of their 1D and 2D NMR spectroscopic and HR/MS spectrometric data. All the compounds were evaluated for their in vitro biological activity against bloodstream forms of Trypanosoma brucei rhodesiense and for cytotoxicity against the mammalian cell line L6. Vernodalin (2) was the most active compound with an IC₅₀ value of 0.16 µM and a selectivity index of 35. Its closely related congener 11β,13-dihydrovernodalin (3) registered an IC₅₀ value of 1.1 µM and a selectivity index of 4.2. Full article

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7 pages, 1266 KiB

Open AccessFeature PaperArticle

Arnica Tincture Cures Cutaneous Leishmaniasis in Golden Hamsters

by Sara M. Robledo, Ivan D. Vélez and Thomas J. Schmidt

Molecules 2018, 23(1), 150; https://doi.org/10.3390/molecules23010150 - 12 Jan 2018

Cited by 8 | Viewed by 5290

Abstract

In search for potential therapeutic alternatives to existing treatments for cutaneous Leishmaniasis, we have investigated the effect of Arnica tincture Ph. Eur. (a 70% hydroethanolic tincture prepared from flowerheads of Arnica montana L.) on the lesions caused by infection with Leishmania braziliensis in [...] Read more.

In search for potential therapeutic alternatives to existing treatments for cutaneous Leishmaniasis, we have investigated the effect of Arnica tincture Ph. Eur. (a 70% hydroethanolic tincture prepared from flowerheads of Arnica montana L.) on the lesions caused by infection with Leishmania braziliensis in a model with golden hamsters. The animals were treated topically with a daily single dose of the preparation for 28 days. Subsequently, the healing process was monitored by recording the lesion size in intervals of 15 days up to day 90. As a result, Arnica tincture fully cured three out of five hamsters while one animal showed an improvement and another one suffered from a relapse. This result was slightly better than that obtained with the positive control, meglumine antimonate, which cured two of five hamsters while the other three showed a relapse after 90 days. This result encourages us to further investigate the potential of Arnica tincture in the treatment of cutaneous Leishmaniasis. Full article

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2017

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420 KiB

Open AccessArticle

Antimalarial Activity of Acetylenic Thiophenes from Echinops hoehnelii Schweinf

by Helen Bitew, Wendimagegn Mammo, Ariaya Hymete and Mariamawit Yonathan Yeshak

Molecules 2017, 22(11), 1965; https://doi.org/10.3390/molecules22111965 - 21 Nov 2017

Cited by 13 | Viewed by 4793

Abstract

Malaria is one of the world’s most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds [...] Read more.

Malaria is one of the world’s most severe endemic diseases and due to the emergence of resistance to the currently available medicines, the need for new targets and relevant antimalarial drugs remains acute. The crude extract, four solvent fractions and two isolated compounds from the roots of Echinops hoehnelii were tested for their antimalarial activity using the standard four-day suppressive method in Plasmodium berghei-infected mice. The 80% methanol extract exhibited suppression of 4.6%, 27.8%, 68.5% and 78.7% at dose of 50, 100, 200 and 400 mg/kg respectively. The dichloromethane fraction displayed chemosuppression of 24.9, 33.5 and 43.0% dose of 100, 200 and 400 mg/kg of body weight. Five acetylenicthiophenes were isolated from the dichloromethane fraction of which 5-(penta-1,3-diynyl)-2-(3,4-dihydroxybut-1-ynyl)-thiophene decreased the level of parasitaemia by 43.2% and 50.2% while 5-(penta-1,3-diynyl)-2-(3-chloro-4-acetoxy-but-1-yn)-thiophene suppressed by 18.8% and 32.7% at 50 and 100 mg/kg, respectively. The study confirmed the traditional claim of the plant to treat malaria and could be used as a new lead for the development of antimalarial drugs. Full article

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1647 KiB

Open AccessArticle

Baccharis reticularia DC. and Limonene Nanoemulsions: Promising Larvicidal Agents for Aedes aegypti (Diptera: Culicidae) Control

by Gisele Da S. Botas, Rodrigo A. S. Cruz, Fernanda B. De Almeida, Jonatas L. Duarte, Raquel S. Araújo, Raimundo Nonato P. Souto, Ricardo Ferreira, José Carlos T. Carvalho, Marcelo G. Santos, Leandro Rocha, Vera Lúcia P. Pereira and Caio P. Fernandes

Molecules 2017, 22(11), 1990; https://doi.org/10.3390/molecules22111990 - 17 Nov 2017

Cited by 68 | Viewed by 6296

Abstract

Baccharis reticularia DC. is a plant species from the Asteraceae family that is endemic to Brazil. Despite the great importance of Baccharis genus, no study has been carried out regarding either the phytochemical composition of B. reticularia or the evaluation of its larvicidal [...] Read more.

Baccharis reticularia DC. is a plant species from the Asteraceae family that is endemic to Brazil. Despite the great importance of Baccharis genus, no study has been carried out regarding either the phytochemical composition of B. reticularia or the evaluation of its larvicidal potential. Considering the intrinsic immiscibility of essential oils, this study shows larvicidal nanoemulsions containing the B. reticularia phytochemically characterized essential oil and its main constituent against Aedes aegypti. The major compound found was d-limonene (25.7%). The essential oil inhibited the acetylcholinesterase, one of the main targets of insecticides. The required hydrophile-lipophile balance of both nanoemulsions was 15.0. The mean droplet sizes were around 90.0 nm, and no major alterations were observed after 24 h of preparation for both formulations. After 48 h of treatment, the estimated LC₅₀ values were 118.94 μg mL⁻¹ and 81.19 μg mL⁻¹ for B. reticularia essential oil and d-limonene nanoemulsions, respectively. Morphological alterations evidenced by scanning electron micrography were observed on the larvae treated with the d-limonene nanoemulsion. This paper demonstrated a simple and ecofriendly method for obtaining B. reticularia essential oil and d-limonene aqueous nanoemulsions by a non-heating and solvent-free method, as promising alternatives for Aedes aegypti control. Full article

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667 KiB

Open AccessArticle

Four Prenylflavone Derivatives with Antiplasmodial Activities from the Stem of Tephrosia purpurea subsp. leptostachya

by Yoseph Atilaw, Lois Muiva-Mutisya, Albert Ndakala, Hoseah M. Akala, Redemptah Yeda, Yu J. Wu, Paolo Coghi, Vincent K. W. Wong, Máté Erdélyi and Abiy Yenesew

Molecules 2017, 22(9), 1514; https://doi.org/10.3390/molecules22091514 - 10 Sep 2017

Cited by 12 | Viewed by 6094

Abstract

Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5–11), were isolated from the [...] Read more.

Four new flavones with modified prenyl groups, namely (E)-5-hydroxytephrostachin (1), purleptone (2), (E)-5-hydroxyanhydrotephrostachin (3), and terpurlepflavone (4), along with seven known compounds (5–11), were isolated from the CH₂Cl₂/MeOH (1:1) extract of the stem of Tephrosia purpurea subsp. leptostachya, a widely used medicinal plant. Their structures were elucidated on the basis of NMR spectroscopic and mass spectrometric evidence. Some of the isolated compounds showed antiplasmodial activity against the chloroquine-sensitive D6 strains of Plasmodium falciparum, with (E)-5-hydroxytephrostachin (1) being the most active, IC₅₀ 1.7 ± 0.1 μM, with relatively low cytotoxicity, IC₅₀ > 21 μM, against four cell-lines. Full article

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1106 KiB

Open AccessArticle

Extracts Obtained from Pterocarpus angolensis DC and Ziziphus mucronata Exhibit Antiplasmodial Activity and Inhibit Heat Shock Protein 70 (Hsp70) Function

by Tawanda Zininga, Chinedu P. Anokwuru, Muendi T. Sigidi, Milingoni P. Tshisikhawe, Isaiah I. D. Ramaite, Afsatou N. Traoré, Heinrich Hoppe, Addmore Shonhai and Natasha Potgieter

Molecules 2017, 22(8), 1224; https://doi.org/10.3390/molecules22081224 - 28 Jul 2017

Cited by 13 | Viewed by 5516

Abstract

Malaria parasites are increasingly becoming resistant to currently used antimalarial therapies, therefore there is an urgent need to expand the arsenal of alternative antimalarial drugs. In addition, it is also important to identify novel antimalarial drug targets. In the current study, extracts of [...] Read more.

Malaria parasites are increasingly becoming resistant to currently used antimalarial therapies, therefore there is an urgent need to expand the arsenal of alternative antimalarial drugs. In addition, it is also important to identify novel antimalarial drug targets. In the current study, extracts of two plants, Pterocarpus angolensis and Ziziphus mucronata were obtained and their antimalarial functions were investigated. Furthermore, we explored the capability of the extracts to inhibit Plasmodium falciparum heat shock protein 70 (Hsp70) function. Heat shock protein 70 (Hsp70) are molecular chaperones whose function is to facilitate protein folding. Plasmodium falciparum the main agent of malaria, expresses two cytosol-localized Hsp70s: PfHsp70-1 and PfHsp70-z. The PfHsp70-z has been reported to be essential for parasite survival, while inhibition of PfHsp70-1 function leads to parasite death. Hence both PfHsp70-1 and PfHsp70-z are potential antimalarial drug targets. Extracts of P. angolensis and Z. mucronata inhibited the basal ATPase and chaperone functions of the two parasite Hsp70s. Furthermore, fractions of P. angolensis and Z. mucronata inhibited P. falciparum 3D7 parasite growth in vitro. The extracts obtained in the current study exhibited antiplasmodial activity as they killed P. falciparum parasites maintained in vitro. In addition, the findings further suggest that some of the compounds in P. angolensis and Z. mucronata may target parasite Hsp70 function. Full article

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722 KiB

Open AccessArticle

Steroid Alkaloids from Holarrhena africana with Strong Activity against Trypanosoma brucei rhodesiense

by Charles Okeke Nnadi, Ngozi Justina Nwodo, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2017, 22(7), 1129; https://doi.org/10.3390/molecules22071129 - 6 Jul 2017

Cited by 35 | Viewed by 7105

Abstract

In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, “sleeping sickness”), we have investigated extracts from the leaves and bark of the West African Holarrhena africana (syn. Holarrhena floribunda; Apocynaceae). The [...] Read more.

In our continued search for natural compounds with activity against Trypanosoma brucei, causative agent of human African trypanosomiasis (HAT, “sleeping sickness”), we have investigated extracts from the leaves and bark of the West African Holarrhena africana (syn. Holarrhena floribunda; Apocynaceae). The extracts and their alkaloid-enriched fractions displayed promising in vitro activity against bloodstream forms of T. brucei rhodesiense (Tbr; East African HAT). Bioactivity-guided chromatographic fractionation of the alkaloid-rich fractions resulted in the isolation of 17 steroid alkaloids, one nitrogen-free steroid and one alkaloid-like non-steroid. Impressive activities (IC₅₀ in µM) against Tbr were recorded for 3β-holaphyllamine (0.40 ± 0.28), 3α-holaphyllamine (0.37 ± 0.16), 3β-dihydroholaphyllamine (0.67 ± 0.03), N-methylholaphyllamine (0.08 ± 0.01), conessimine (0.17 ± 0.08), conessine (0.42 ± 0.09), isoconessimine (0.17 ± 0.11) and holarrhesine (0.12 ± 0.08) with selectivity indices ranging from 13 to 302. Based on comparison of the structures of this congeneric series of steroid alkaloids and their activities, structure-activity relationships (SARs) could be established. It was found that a basic amino group at position C-3 of the pregnane or pregn-5-ene steroid nucleus is required for a significant anti-trypanosomal activity. The mono-methylated amino group at C-3 represents an optimum for activity. ∆^5,6 unsaturation slightly increased the activity while hydrolysis of C-12β ester derivatives led to a loss of activity. An additional amino group at C-20 engaged in a pyrrolidine ring closed towards C-18 significantly increased the selectivity index of the compounds. Our findings provide useful empirical data for further development of steroid alkaloids as a novel class of anti-trypanosomal compounds which represent a promising starting point towards new drugs to combat human African trypanosomiasis. Full article

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1770 KiB

Open AccessArticle

Leishmanicidal Activity and Structure-Activity Relationships of Essential Oil Constituents

by Audrey R. S. T. Silva, Ricardo Scher, Flaviane V. Santos, Sebastião R. Ferreira, Sócrates C. H. Cavalcanti, Cristiane B. Correa, Lilian L. Bueno, Ricardo J. Alves, Damião P. Souza, Ricardo T. Fujiwara and Silvio S. Dolabella

Molecules 2017, 22(5), 815; https://doi.org/10.3390/molecules22050815 - 16 May 2017

Cited by 40 | Viewed by 5724

Abstract

Several constituents of essential oils have been shown to be active against pathogens such as bacteria, fungi, and protozoa. This study demonstrated the in vitro action of ten compounds present in essential oils against Leishmania amazonensis promastigotes. With the exception of p-cymene, [...] Read more.

Several constituents of essential oils have been shown to be active against pathogens such as bacteria, fungi, and protozoa. This study demonstrated the in vitro action of ten compounds present in essential oils against Leishmania amazonensis promastigotes. With the exception of p-cymene, all evaluated compounds presented leishmanicidal activity, exhibiting IC₅₀ between 25.4 and 568.1 μg mL⁻¹. Compounds with the best leishmanicidal activity presented a phenolic moiety (IC₅₀ between 25.4 and 82.9 μg mL⁻¹). Alicyclic alcohols ((−)-menthol and isoborneol) and ketones ((−)-carvone) promoted similar activity against the parasite (IC₅₀ between 190.2 and 198.9 μg mL⁻¹). Most of the compounds showed low cytotoxicity in L929 fibroblasts. Analysis of the structure-activity relationship of these compounds showed the importance of the phenolic structure for the biological action against the promastigote forms of the parasite. Full article

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Open AccessArticle

Alkamides from Anacyclus pyrethrum L. and Their in Vitro Antiprotozoal Activity

by Julia B. Althaus, Claudine Malyszek, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2017, 22(5), 796; https://doi.org/10.3390/molecules22050796 - 12 May 2017

Cited by 21 | Viewed by 5794

Abstract

In our ongoing study to evaluate the antiprotozoal activity of alkamides from Asteraceae, a dichloromethane extract from the roots of Anacyclus pyrethrum L. showed a moderate in vitro activity against the NF54 strain of Plasmodium falciparum and against Leishmania donovani (amastigotes, MHOM/ET/67/L82 strain). [...] Read more.

In our ongoing study to evaluate the antiprotozoal activity of alkamides from Asteraceae, a dichloromethane extract from the roots of Anacyclus pyrethrum L. showed a moderate in vitro activity against the NF54 strain of Plasmodium falciparum and against Leishmania donovani (amastigotes, MHOM/ET/67/L82 strain). Seven pure alkamides and a mixture of two further alkamides were isolated by column chromatography followed by preparative high performance liquid chromatography. The alkamides were identified by mass- and NMR-spectroscopic methods as tetradeca-2E,4E-dien-8,10-diynoic acid isobutylamide (anacycline, 1), deca-2E,4E-dienoic acid isobutylamide (pellitorine, 2), deca-2E,4E,9-trienoic acid isobutylamide (3), deca-2E,4E-dienoic acid 2-phenylethylamide (4), undeca-2E,4E-dien-8,10-diynoic acid isopentylamide (5), tetradeca-2E,4E,12Z-trien-8,10-diynoic acid isobutylamide (6), and dodeca-2E,4E-dien acid 4-hydroxy-2-phenylethylamide (7). Two compounds—undeca-2E,4E-dien-8,10-diynoic acid 2-phenylethylamide (8) and deca-2E,4E-dienoic acid 4-hydroxy-2-phenylethylamide (9)—were isolated as an inseparable mixture (1:4). Compounds 3, 4, and 5 were isolated from Anacyclus pyrethrum L. for the first time. While compounds 4 and 5 were previously known from the genus Achillea, compound 3 is a new natural product, to the best of our knowledge. All isolated alkamides were tested in vitro for antiprotozoal activity against Plasmodium falciparum, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani and for cytotoxicity against L6 rat skeletal myoblasts. Full article

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828 KiB

Open AccessArticle

Anti-Onchocerca and Anti-Caenorhabditis Activity of a Hydro-Alcoholic Extract from the Fruits of Acacia nilotica and Some Proanthocyanidin Derivatives

by Jacqueline Dikti Vildina, Justin Kalmobe, Boursou Djafsia, Thomas J. Schmidt, Eva Liebau and Dieudonne Ndjonka

Molecules 2017, 22(5), 748; https://doi.org/10.3390/molecules22050748 - 6 May 2017

Cited by 27 | Viewed by 5719

Abstract

Acacia nilotica fruits with high tannin content are used in the northern parts of Cameroon as anti-filarial remedies by traditional healers. In this study, the hydro-alcoholic fruit extract (crude extract (CE)) and, one of the main constituents in its most active fractions, (+)-catechin-3- [...] Read more.

Acacia nilotica fruits with high tannin content are used in the northern parts of Cameroon as anti-filarial remedies by traditional healers. In this study, the hydro-alcoholic fruit extract (crude extract (CE)) and, one of the main constituents in its most active fractions, (+)-catechin-3-O-gallate (CG), as well as four related proanthocyanidins, (−)-epicatechin-3-O-gallate (ECG), (+)-gallocatechin (GC), (−)-epigallocatechin (EGC) and (−)-epigallocatechin-3-O-gallate (EGCG), were assessed for their potential in vitro anthelmintic properties against the free-living model organism Caenorhabditis elegans and against the cattle filarial parasite Onchocerca ochengi. Worms were incubated in the presence of different concentrations of fruit extract, fractions and pure compounds. The effects on mortality were monitored after 48 h. The plant extract and all of the pure tested compounds were active against O. ochengi (LC₅₀ ranging from 1.2 to 11.5 µg/mL on males) and C. elegans (LC₅₀ ranging from 33.8 to 350 µg/mL on wild type). While high LC₅₀ were required for the effects of the compounds on C. elegans, very low LC₅₀ were required against O. ochengi. Importantly, tests for acute oral toxicity (lowest dose: 10 mg/kg) in Wistar rats demonstrated that crude extract and pure compounds were non-toxic and safe to use. Additionally, the results of cytotoxicity tests with the Caco-2 cell line (CC₅₀ ranging from 47.1 to 93.2 µg/mL) confirmed the absence of significant toxicity of the crude extract and pure compounds. These results are in good accordance with the use of A. nilotica against nematode infections by traditional healers, herdsmen and pastoralists in Cameroon. Full article

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2557 KiB

Open AccessArticle

Investigation of the Anti-Leishmania (Leishmania) infantum Activity of Some Natural Sesquiterpene Lactones

by Imke F. Wulsten, Thais A. Costa-Silva, Juliana T. Mesquita, Marta L. Lima, Mariana K. Galuppo, Noemi N. Taniwaki, Samanta E. T. Borborema, Fernando B. Da Costa, Thomas J. Schmidt and Andre G. Tempone

Molecules 2017, 22(5), 685; https://doi.org/10.3390/molecules22050685 - 25 Apr 2017

Cited by 22 | Viewed by 6657

Abstract

Leishmaniases are neglected infectious diseases caused by parasites of the ‘protozoan’ genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the [...] Read more.

Leishmaniases are neglected infectious diseases caused by parasites of the ‘protozoan’ genus Leishmania. Depending on the parasite species, different clinical forms are known as cutaneous, muco-cutaneous, and the visceral leishmaniasis (VL). VL is particularly fatal and the therapy presents limitations. In the search for new anti-leishmanial hit compounds, seven natural sesquiterpene lactones were evaluated against promastigotes and intracellular amastigotes of Leishmania (Leishmania) infantum, a pathogen causing VL. The pseudoguaianolides mexicanin I and helenalin acetate demonstrated the highest selectivity and potency against intracellular amastigotes. In addition, promastigotes treated with helenalin acetate were subject to an ultrastructural and biochemical investigation. The lethal action of the compound was investigated by fluorescence-activated cell sorting and related techniques to detect alterations in reactive oxygen species (ROS) content, plasma membrane permeability, and mitochondrial membrane potential. Helenalin acetate significantly reduced the mitochondrial membrane potential and the mitochondrial structural damage was also confirmed by transmission electron microscopy, displaying an intense organelle swelling. No alteration of plasma membrane permeability or ROS content could be detected. Additionally, helenalin acetate significantly increased the production of nitric oxide in peritoneal macrophages, probably potentiating the activity against the intracellular amastigotes. Helenalin acetate could hence be a useful anti-leishmanial scaffold for further optimization studies. Full article

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2720 KiB

Open AccessReview

Potential Antivirals: Natural Products Targeting Replication Enzymes of Dengue and Chikungunya Viruses

by Ana Flávia Costa da Silveira Oliveira, Róbson Ricardo Teixeira, André Silva de Oliveira, Ana Paula Martins de Souza, Milene Lopes da Silva and Sérgio Oliveira de Paula

Molecules 2017, 22(3), 505; https://doi.org/10.3390/molecules22030505 - 22 Mar 2017

Cited by 63 | Viewed by 10472

Abstract

Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations [...] Read more.

Dengue virus (DENV) and chikungunya virus (CHIKV) are reemergent arboviruses that are transmitted by mosquitoes of the Aedes genus. During the last several decades, these viruses have been responsible for millions of cases of infection and thousands of deaths worldwide. Therefore, several investigations were conducted over the past few years to find antiviral compounds for the treatment of DENV and CHIKV infections. One attractive strategy is the screening of compounds that target enzymes involved in the replication of both DENV and CHIKV. In this review, we describe advances in the evaluation of natural products targeting the enzymes involved in the replication of these viruses. Full article

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Open AccessReview

Computer-Aided Drug Design Using Sesquiterpene Lactones as Sources of New Structures with Potential Activity against Infectious Neglected Diseases

by Chonny Herrera Acevedo, Luciana Scotti, Mateus Feitosa Alves, Margareth De Fátima Formiga Melo Diniz and Marcus Tullius Scotti

Molecules 2017, 22(1), 79; https://doi.org/10.3390/molecules22010079 - 3 Jan 2017

Cited by 32 | Viewed by 9051

Abstract

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, [...] Read more.

This review presents an survey to the biological importance of sesquiterpene lactones (SLs) in the fight against four infectious neglected tropical diseases (NTDs)—leishmaniasis, schistosomiasis, Chagas disease, and sleeping sickness—as alternatives to the current chemotherapies that display several problems such as low effectiveness, resistance, and high toxicity. Several studies have demonstrated the great potential of some SLs as therapeutic agents for these NTDs and the relationship between the protozoal activities with their chemical structure. Recently, Computer-Aided Drug Design (CADD) studies have helped increase the knowledge of SLs regarding their mechanisms, the discovery of new lead molecules, the identification of pharmacophore groups and increase the biological activity by employing in silico tools such as molecular docking, virtual screening and Quantitative-Structure Activity Relationship (QSAR) studies. Full article

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2016

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543 KiB

Open AccessArticle

Evaluation of Chemical Composition and Antileishmanial and Antituberculosis Activities of Essential Oils of Piper Species

by Karine Zanoli Bernuci, Camila Cristina Iwanaga, Carla Maria Mariano Fernandez-Andrade, Fabiana Brusco Lorenzetti, Eduardo Caio Torres-Santos, Viviane Dos Santos Faiões, José Eduardo Gonçalves, Wanderlei Do Amaral, Cícero Deschamps, Regiane Bertin de Lima Scodro, Rosilene Fressatti Cardoso, Vanessa Pietrowski Baldin and Diógenes Aparício Garcia Cortez

Molecules 2016, 21(12), 1698; https://doi.org/10.3390/molecules21121698 - 12 Dec 2016

Cited by 54 | Viewed by 7294

Abstract

Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC–MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority [...] Read more.

Essential oils from fresh Piperaceae leaves were obtained by hydrodistillation and analyzed by gas chromatography mass spectrometry (GC–MS), and a total of 68 components were identified. Principal components analysis results showed a chemical variability between species, with sesquiterpene compounds predominating in the majority of species analyzed. The composition of the essential oil of Piper mosenii was described for the first time. The cytotoxicity of the essential oils was evaluated in peritoneal macrophages and the oils of P. rivinoides, P. arboretum, and P. aduncum exhibited the highest values, with cytotoxic concentration at 50% (CC₅₀) > 200 µg/mL. Both P. diospyrifolium and P. aduncum displayed activity against Leishmania amazonensis, and were more selective for the parasite than for the macrophages, with a selectivity index (SI) of 2.35 and >5.52, respectively. These SI values were greater than the 1 for the standard drug pentamidine. The antileishmanial activity of the essential oils of P. diospyrifolium and P. aduncum was described for the first time. P. rivinoides, P. cernuum, and P. diospyrifolium displayed moderate activity against the Mycobacterium tuberculosis H₃₇Rv bacillus, with a minimum inhibitory concentration (MIC) of 125 µg/mL. These results are relevant and suggests their potential for therapeutic purposes. Nevertheless, further studies are required to explain the exact mechanism of action of these essential oils. Full article

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Open AccessReview

The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases—Part III: In-Silico Molecular Docking Investigations

by Ifedayo Victor Ogungbe and William N. Setzer

Molecules 2016, 21(10), 1389; https://doi.org/10.3390/molecules21101389 - 19 Oct 2016

Cited by 33 | Viewed by 12302

Abstract

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a [...] Read more.

Malaria, leishmaniasis, Chagas disease, and human African trypanosomiasis continue to cause considerable suffering and death in developing countries. Current treatment options for these parasitic protozoal diseases generally have severe side effects, may be ineffective or unavailable, and resistance is emerging. There is a constant need to discover new chemotherapeutic agents for these parasitic infections, and natural products continue to serve as a potential source. This review presents molecular docking studies of potential phytochemicals that target key protein targets in Leishmania spp., Trypanosoma spp., and Plasmodium spp. Full article

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407 KiB

Open AccessArticle

Antiprotozoal and Antiglycation Activities of Sesquiterpene Coumarins from Ferula narthex Exudate

by Adnan Amin, Emmy Tuenter, Paul Cos, Louis Maes, Vassiliki Exarchou, Sandra Apers and Luc Pieters

Molecules 2016, 21(10), 1287; https://doi.org/10.3390/molecules21101287 - 26 Sep 2016

Cited by 31 | Viewed by 5851

Abstract

The exudate of Ferula narthex Boiss. (Apiaceae) is widely used in the Indian subcontinent as a spice and because of its health effects. Six sesquiterpene coumarins have been isolated from this exudate: feselol, ligupersin A, asacoumarin A, 8′-O-acetyl-asacoumarin A, 10′R [...] Read more.

The exudate of Ferula narthex Boiss. (Apiaceae) is widely used in the Indian subcontinent as a spice and because of its health effects. Six sesquiterpene coumarins have been isolated from this exudate: feselol, ligupersin A, asacoumarin A, 8′-O-acetyl-asacoumarin A, 10′R-karatavacinol and 10′R-acetyl-karatavacinol. Based on its use in infectious and diabetic conditions, the isolated constituents were evaluated for antimicrobial and antiglycation activities. Some compounds showed activity against protozoal parasites, asacoumarin A being the most active one against Plasmodium falciparum K1 (IC₅₀ 1.3 μM). With regard to antiglycation activity, in the BSA-glucose test, ligupersin A displayed the highest activity (IC₅₀ 0.41 mM), being more active than the positive control aminiguanidine (IC₅₀ 1.75 mM). In the BSA-MGO assay, the highest activity was shown by 8′-O-acetyl-asacoumarin A (IC₅₀ 1.03 mM), being less active than aminoguanidine (IC₅₀ 0.15 mM). Hence, the antiglycation activity of the isolated constituents was due to both oxidative and non-oxidative modes of inhibition. Full article

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1134 KiB

Open AccessArticle

ent-Pimarane and ent-Kaurane Diterpenes from Aldama discolor (Asteraceae) and Their Antiprotozoal Activity

by Mauro S. Nogueira, Fernando B. Da Costa, Reto Brun, Marcel Kaiser and Thomas J. Schmidt

Molecules 2016, 21(9), 1237; https://doi.org/10.3390/molecules21091237 - 15 Sep 2016

Cited by 24 | Viewed by 6732

Abstract

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian “Cerrado”, which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to [...] Read more.

Aldama discolor (syn.Viguiera discolor) is an endemic Asteraceae from the Brazilian “Cerrado”, which has not previously been investigated for its chemical constituents and biological activity. Diterpenes are common secondary metabolites found in Aldama species, some of which have been reported to present potential antiprotozoal and antimicrobial activities. In this study, the known ent-3-α-hydroxy-kaur-16-en-18-ol (1), as well as three new diterpenes, namely, ent-7-oxo-pimara-8,15-diene-18-ol (2), ent-2S,4S-2-19-epoxy-pimara-8(3),15-diene-7β-ol (3) and ent-7-oxo-pimara-8,15-diene-3β-ol (4), were isolated from the dichloromethane extract of A. discolor leaves and identified by means of MS and NMR. The compounds were assayed in vitro against Trypanosoma brucei rhodesiense, T. cruzi and Leishmania donovani, Plasmodium falciparum and also tested for cytotoxicity against mammalian cells (L6 cell line). The ent-kaurane 1 showed significant in vitro activity against both P. falciparum (IC

_{50}

= 3.5

μ

M) and L. donovani (IC

_{50}

= 2.5

μ

M) and ent-pimarane 2 against P. falciparum (IC

_{50}

= 3.8

μ

M). Both compounds returned high selectivity indices (SI >10) in comparison with L6 cells, which makes them interesting candidates for in vivo tests. In addition to the diterpenes, the sesquiterpene lactone budlein A (5), which has been reported to possess a strong anti-T. b. rhodesiense activity, was identified as major compound in the A. discolor extract and explains its high activity against this parasite (100% growth inhibition at 2

μ

g/mL). Full article

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Open AccessArticle

Antidiarrheal Thymol Derivatives from Ageratina glabrata. Structure and Absolute Configuration of 10-Benzoyloxy-8,9-epoxy-6-hydroxythymol Isobutyrate

by Celia Bustos-Brito, Valeria J. Vázquez-Heredia, Fernando Calzada, Lilian Yépez-Mulia, José S. Calderón, Simón Hernández-Ortega, Baldomero Esquivel, Normand García-Hernández and Leovigildo Quijano

Molecules 2016, 21(9), 1132; https://doi.org/10.3390/molecules21091132 - 12 Sep 2016

Cited by 13 | Viewed by 6161

Abstract

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with [...] Read more.

Chemical investigation of the leaves from Ageratina glabrata yielded four new thymol derivatives, namely: 10-benzoyloxy-8,9-dehydro-6-hydroxythymol isobutyrate (4), 10-benzoyloxy-8,9-dehydrothymol (5), 10-benzoyloxythymol (6) and 10-benzoyloxy-6,8-dihydroxy-9-isobutyryl-oxythymol (7). In addition, (8S)-10-benzoyloxy-8,9-epoxy-6-hydroxythymol isobutyrate (1), together with other two already known thymol derivatives identified as 10-benzoyloxy-8,9-epoxy-6-methoxythymol isobutyrate (2) and 10-benzoyloxy-8,9-epoxythymol isobutyrate (3) were also obtained. In this paper, we report the structures and complete assignments of the ¹H and ¹³C-NMR data of compounds 1–7, and the absolute configuration for compound 1, unambiguously established by single crystal X-ray diffraction, and evaluation of the Flack parameter. The in vitro antiprotozoal assay showed that compound 1 and its derivative 1a were the most potent antiamoebic and antigiardial compounds. Both compounds showed selectivity and good antiamoebic activity comparable to emetine and metronidazole, respectively, two antiprotozoal drugs used as positive controls. In relation to anti-propulsive effect, compound 1 and 1a showed inhibitory activity, with activities comparable to quercetin and compound 9, two natural antipropulsive compounds used as positive controls. These data suggest that compound 1 may play an important role in antidiarrheal properties of Ageratina glabrata. Full article

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387 KiB

Open AccessCommunication

In Vitro Antileishmanial Activity of Sterols from Trametes versicolor (Bres. Rivarden)

by Vivian Leliebre-Lara, Lianet Monzote Fidalgo, Eva-Maria Pferschy-Wenzig, Olaf Kunert, Clara Nogueiras Lima and Rudolf Bauer

Molecules 2016, 21(8), 1045; https://doi.org/10.3390/molecules21081045 - 10 Aug 2016

Cited by 29 | Viewed by 6404

Abstract

Two ergostanes, 5α,8α-epidioxy-22E-ergosta-6,22-dien-3β-ol (1) and 5α-ergost-7,22-dien-3β-ol (2), and a lanostane, 3β-hydroxylanostan-8,24-diene-21-oic acid (trametenolic acid) (3), were isolated from an n-hexane extract prepared from the fruiting body of Trametes versicolor (Bres. Rivarden). The activity of [...] Read more.

Two ergostanes, 5α,8α-epidioxy-22E-ergosta-6,22-dien-3β-ol (1) and 5α-ergost-7,22-dien-3β-ol (2), and a lanostane, 3β-hydroxylanostan-8,24-diene-21-oic acid (trametenolic acid) (3), were isolated from an n-hexane extract prepared from the fruiting body of Trametes versicolor (Bres. Rivarden). The activity of the isolated sterols was evaluated against promastigotes and amastigotes of Leishmania amazonensis Lainson and Shaw, 1972. The lanostane, compound (3), showed the best inhibitory response (IC₅₀ promastigotes 2.9 ± 0.1 μM and IC₅₀ amastigotes 1.6 ± 0.1 μM). This effect was 25-fold higher compared with its cytotoxic effect on peritoneal macrophages from BALB/c mice. Therefore, trametenolic acid could be regarded as a promising lead for the synthesis of compounds with antileishmanial activity. Full article

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Open AccessArticle

In Vitro Reversible and Time-Dependent CYP450 Inhibition Profiles of Medicinal Herbal Plant Extracts Newbouldia laevis and Cassia abbreviata: Implications for Herb-Drug Interactions

by Nicholas Ekow Thomford, Kevin Dzobo, Denis Chopera, Ambroise Wonkam, Alfred Maroyi, Dee Blackhurst and Collet Dandara

Molecules 2016, 21(7), 891; https://doi.org/10.3390/molecules21070891 - 7 Jul 2016

Cited by 32 | Viewed by 8538

Abstract

This study evaluated the effects of Newbouldia laevis and Cassia abbreviata extracts on CYP450 enzyme activity. Recombinant CYP450 enzyme and fluorogenic substrates were used for evaluating inhibition, allowing the assessment of herb–drug interactions (HDI). Phytochemical fingerprinting was performed using UPLC-MS. The herbal extracts [...] Read more.

This study evaluated the effects of Newbouldia laevis and Cassia abbreviata extracts on CYP450 enzyme activity. Recombinant CYP450 enzyme and fluorogenic substrates were used for evaluating inhibition, allowing the assessment of herb–drug interactions (HDI). Phytochemical fingerprinting was performed using UPLC-MS. The herbal extracts were risk ranked for HDI based on the IC₅₀ values determined for each CYP enzyme. Newbouldia laevis inhibited CYP1A2, CYP2C9, and CYP2C19 enzyme activities with K_i of 2.84 µg/mL, 1.55 µg/mL, and 1.23 µg/mL, respectively. N. laevis exhibited a TDI (4.17) effect on CYP1A2 but not CYP2C9 and CYP2C19 enzyme activities. Cassia abbreviata inhibited CYP1A2, CYP2C9, and CYP2C19 enzyme activities showing a K_i of 4.86 µg/mL, 5.98 µg/mL, and 1.58 µg/mL, respectively. TDI potency assessment for Cassia abbreviata showed it as a potential TDI candidate (1.64) for CYP1A2 and CYP2C19 (1.72). UPLC-MS analysis showed that Newbouldia laevis and Cassia abbreviata possess polyphenols that likely give them their therapeutic properties; some of them are likely to be responsible for the observed inhibition. The observations made in this study suggest the potential for these herbal compounds to interact, especially when co-administered with other medications metabolized by these CYP450 enzymes. Full article

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Open AccessFeature PaperArticle

A New Alkamide with an Endoperoxide Structure from Acmella ciliata (Asteraceae) and Its in Vitro Antiplasmodial Activity

by Narjara Silveira, Julia Saar, Alan Diego C. Santos, Andersson Barison, Louis P. Sandjo, Marcel Kaiser, Thomas J. Schmidt and Maique W. Biavatti

Molecules 2016, 21(6), 765; https://doi.org/10.3390/molecules21060765 - 11 Jun 2016

Cited by 21 | Viewed by 7885

Abstract

From the aerial parts of Acmella ciliata (H.B.K.) Cassini (basionym Spilanthes ciliata Kunth; Asteraceae), three alkamides were isolated and identified by mass- and NMR spectroscopic methods as (2E,6E,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), N-(2-phenethyl)-2E [...] Read more.

From the aerial parts of Acmella ciliata (H.B.K.) Cassini (basionym Spilanthes ciliata Kunth; Asteraceae), three alkamides were isolated and identified by mass- and NMR spectroscopic methods as (2E,6E,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), N-(2-phenethyl)-2E-en-6,8-nonadiynamide (2) and (2E,7Z)-6,9-endoperoxy-N-isobutyl-2,7-decadienamide (3). While 1 and 2 are known alkamides, compound 3 has not been described until now. It was found that the unusual cyclic peroxide 3 exists as a racemate of both enantiomers of each alkamide; the 6,9-cis- as well as the 6,9-trans-configured diastereomers, the former represents the major, the latter the minor constituent of the mixture. In vitro tests for activity against the human pathogenic parasites Trypanosoma brucei rhodesiense and Plasmodium falciparum revealed that 1 and 3 possess activity against the NF54 strain of the latter (IC₅₀ values of 4.5 and 5.1 µM, respectively) while 2 was almost inactive. Compound 3 was also tested against multiresistant P. falciparum K1 and was found to be even more active against this parasite strain (IC₅₀ = 2.1 µM) with considerable selectivity (IC₅₀ against L6 rat skeletal myoblasts = 168 µM). Full article

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Open AccessArticle

In Vitro Activity of Selected West African Medicinal Plants against Mycobacterium ulcerans Disease

by Patrick Valere Tsouh Fokou, Abena Adomah Kissi-Twum, Dorothy Yeboah-Manu, Regina Appiah-Opong, Phyllis Addo, Lauve Rachel Tchokouaha Yamthe, Alvine Ngoutane Mfopa, Fabrice Fekam Boyom and Alexander Kwadwo Nyarko

Molecules 2016, 21(4), 445; https://doi.org/10.3390/molecules21040445 - 13 Apr 2016

Cited by 14 | Viewed by 6951

Abstract

Buruli ulcer (BU) is the third most prevalent mycobacteriosis, after tuberculosis and leprosy. The currently recommended combination of rifampicin-streptomycin suffers from side effects and poor compliance, which leads to reliance on local herbal remedies. The objective of this study was to investigate the [...] Read more.

Buruli ulcer (BU) is the third most prevalent mycobacteriosis, after tuberculosis and leprosy. The currently recommended combination of rifampicin-streptomycin suffers from side effects and poor compliance, which leads to reliance on local herbal remedies. The objective of this study was to investigate the antimycobacterial properties and toxicity of selected medicinal plants. Sixty-five extracts from 27 plant species were screened against Mycobacterium ulcerans and Mycobacterium smegmatis, using the Resazurin Microtiter Assay (REMA). The cytotoxicity of promising extracts was assayed on normal Chang liver cells by an MTT assay. Twenty five extracts showed activity with minimal inhibitory concentration (MIC) values ranging from 16 µg/mL to 250 µg/mL against M. smegmatis, while 17 showed activity against M. ulcerans with MIC values ranging from 125 µg/mL to 250 µg/mL. In most of the cases, plant extracts with antimycobacterial activity showed no cytotoxicity on normal human liver cells. Exception were Carica papaya, Cleistopholis patens, and Polyalthia suaveolens with 50% cell cytotoxic concentrations (CC₅₀) ranging from 3.8 to 223 µg/mL. These preliminary results support the use of some West African plants in the treatment of Buruli ulcer. Meanwhile, further studies are required to isolate and characterize the active ingredients in the extracts. Full article

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1299 KiB

Open AccessArticle

Phenolic Constituents of Medicinal Plants with Activity against Trypanosoma brucei

by Ya Nan Sun, Joo Hwan No, Ga Young Lee, Wei Li, Seo Young Yang, Gyongseon Yang, Thomas J. Schmidt, Jong Seong Kang and Young Ho Kim

Molecules 2016, 21(4), 480; https://doi.org/10.3390/molecules21040480 - 12 Apr 2016

Cited by 19 | Viewed by 6492

Abstract

Neglected tropical diseases (NTDs) affect over one billion people all over the world. These diseases are classified as neglected because they impact populations in areas with poor financial conditions and hence do not attract sufficient research investment. Human African Trypanosomiasis (HAT or sleeping [...] Read more.

Neglected tropical diseases (NTDs) affect over one billion people all over the world. These diseases are classified as neglected because they impact populations in areas with poor financial conditions and hence do not attract sufficient research investment. Human African Trypanosomiasis (HAT or sleeping sickness), caused by the parasite Trypanosoma brucei, is one of the NTDs. The current therapeutic interventions for T. brucei infections often have toxic side effects or require hospitalization so that they are not available in the rural environments where HAT occurs. Furthermore, parasite resistance is increasing, so that there is an urgent need to identify novel lead compounds against this infection. Recognizing the wide structural diversity of natural products, we desired to explore and identify novel antitrypanosomal chemotypes from a collection of natural products obtained from plants. In this study, 440 pure compounds from various medicinal plants were tested against T. brucei by in a screening using whole cell in vitro assays. As the result, twenty-two phenolic compounds exhibited potent activity against cultures of T. brucei. Among them, eight compounds—4, 7, 11, 14, 15, 18, 20, and 21—showed inhibitory activity against T. brucei, with IC₅₀ values below 5 µM, ranging from 0.52 to 4.70 μM. Based on these results, we attempt to establish some general trends with respect to structure-activity relationships, which indicate that further investigation and optimization of these derivatives might enable the preparation of potentially useful compounds for treating HAT. Full article

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2015

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3628 KiB

Open AccessArticle

Leishmanicidal Activity of (+)-Phyllanthidine and the Phytochemical Profile of Margaritaria nobilis (Phyllanthaceae)

by Lienne S. Moraes, Marcio R. H. Donza, Ana Paula D. Rodrigues, Bruno J. M. Silva, Davi S. B. Brasil, Maria Das Graças B. Zoghbi, Eloísa H. A. Andrade, Giselle M. S. P. Guilhon and Edilene O. Silva

Molecules 2015, 20(12), 22157-22169; https://doi.org/10.3390/molecules201219829 - 11 Dec 2015

Cited by 25 | Viewed by 7455

Abstract

The effects of the Securinega alkaloid (+)-phyllanthidine on Leishmania (L.) amazonensis and the first chemical investigation of Margaritaria nobilis L.f. (Phyllanthaceae) are described. Treating the parasites with this alkaloid caused a dose-dependent reduction in promastigote growth of 67.68% (IC₅₀ 82.37 μg/mL or [...] Read more.

The effects of the Securinega alkaloid (+)-phyllanthidine on Leishmania (L.) amazonensis and the first chemical investigation of Margaritaria nobilis L.f. (Phyllanthaceae) are described. Treating the parasites with this alkaloid caused a dose-dependent reduction in promastigote growth of 67.68% (IC₅₀ 82.37 μg/mL or 353 µM) and in amastigote growth of 83.96% (IC₅₀ 49.11 μg/mL or 210 µM), together with ultrastructural alterations in the promastigotes. No cytotoxic effect was detected in mammalian cells (CC₅₀ 1727.48 µg/mL or CC₅₀ 5268 µM). Classical chromatographic techniques and spectral methods led to the isolation and identification of betulinic acid, kaempferol, corilagin, gallic acid and its methyl ester, besides (+)-phyllanthidine from M. nobilis leaves and stems. Margaritaria nobilis is another source of the small group of Securinega alkaloids, together with other Phyllanthaceae (Euphorbiaceae s.l.) species. The low toxicity to macrophages and the effects against promastigotes and amastigotes are suggestive that (+)-phyllanthidine could be a promising antileishmanial agent for treating cutaneous leishmaniasis. Full article

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Open AccessCorrection

Lewies, A., et al. The Potential Use of Natural and Structural Analogues of Antimicrobial Peptides in the Fight against Neglected Tropical Diseases. Molecules 2015, 20, 15392–15433

by Angélique Lewies, Johannes F. Wentzel, Garmi Jacobs and Lissinda H. Du Plessis

Molecules 2015, 20(9), 16757; https://doi.org/10.3390/molecules200916757 - 14 Sep 2015

Cited by 6 | Viewed by 4600

Abstract

The authors wish to make the following corrections to this paper [1]: [...] Full article

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Open AccessReview

The Potential Use of Natural and Structural Analogues of Antimicrobial Peptides in the Fight against Neglected Tropical Diseases

by Angélique Lewies, Johannes Frederik Wentzel, Garmi Jacobs and Lissinda Hester Du Plessis

Molecules 2015, 20(8), 15392-15433; https://doi.org/10.3390/molecules200815392 - 24 Aug 2015

Cited by 49 | Viewed by 10629 | Correction

Abstract

Recently, research into the development of new antimicrobial agents has been driven by the increase in resistance to traditional antibiotics and Emerging Infectious Diseases. Antimicrobial peptides (AMPs) are promising candidates as alternatives to current antibiotics in the treatment and prevention of microbial infections. [...] Read more.

Recently, research into the development of new antimicrobial agents has been driven by the increase in resistance to traditional antibiotics and Emerging Infectious Diseases. Antimicrobial peptides (AMPs) are promising candidates as alternatives to current antibiotics in the treatment and prevention of microbial infections. AMPs are produced by all known living species, displaying direct antimicrobial killing activity and playing an important role in innate immunity. To date, more than 2000 AMPs have been discovered and many of these exhibit broad-spectrum antibacterial, antiviral and anti-parasitic activity. Neglected tropical diseases (NTDs) are caused by a variety of pathogens and are particularly wide-spread in low-income and developing regions of the world. Alternative, cost effective treatments are desperately needed to effectively battle these medically diverse diseases. AMPs have been shown to be effective against a variety of NTDs, including African trypanosomes, leishmaniosis and Chagas disease, trachoma and leprosy. In this review, the potential of selected AMPs to successfully treat a variety of NTD infections will be critically evaluated. Full article

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Open AccessArticle

Anti-Protozoal Activities of Cembrane-Type Diterpenes from Vietnamese Soft Corals

by Nguyen Phuong Thao, Bui Thi Thuy Luyen, Reto Brun, Marcel Kaiser, Phan Van Kiem, Chau Van Minh, Thomas J. Schmidt, Jong Seong Kang and Young Ho Kim

Molecules 2015, 20(7), 12459-12468; https://doi.org/10.3390/molecules200712459 - 8 Jul 2015

Cited by 28 | Viewed by 6880

Abstract

Based on our previous finding that certain cembranoid diterpenes possess selective toxicity against protozoan pathogens of tropical diseases such as Trypanosoma and Plasmodium, we have subjected a series of 34 cembranes isolated from soft corals living in the Vietnamese sea to an [...] Read more.

Based on our previous finding that certain cembranoid diterpenes possess selective toxicity against protozoan pathogens of tropical diseases such as Trypanosoma and Plasmodium, we have subjected a series of 34 cembranes isolated from soft corals living in the Vietnamese sea to an in vitro screening for anti-protozoal activity against Trypanosoma brucei rhodesiense (Tbr), T. cruzi (Tc), Leishmania donovani (Ld), and Plasmodium falciparum (Pf). Twelve of the tested compounds displayed significant activity against at least one of the parasites. Specifically, 7S,8S-epoxy-1,3,11-cembratriene-16-oic methyl ester (1), (1R,4R,2E,7E,11E)-cembra-2,7,11-trien-4-ol (2), crassumol D (12), crassumol E (13), and (1S,2E,4S,6E,8S,11S)-2,6,12(20)-cembrantriene-4,8,11-triol (16) from Lobophytum crassum, L. laevigatum, and Sinularia maxima showed the highest level of inhibitory activity against T. b. rhodesiense, with IC₅₀ values of about 1 µM or less. Lobocrasol A (6) and lobocrasol C (8) from L. crassum and L. laevigatum exhibited particularly significant inhibitory effects on L. donovani with IC₅₀ values < 0.2 µM. The best antiplasmodial effect was exerted by laevigatol A (10), with an IC₅₀ value of about 3.0 µM. The cytotoxicity of the active compounds on L6 rat skeletal myoblast cell was also assessed and found to be insignificant in all cases. This is the first report on anti-protozoal activity of these compounds, and points out the potential of the soft corals in discovery of new anti-protozoal lead compounds. Full article

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Open AccessArticle

Anti-Schistosomal Activity of Cinnamic Acid Esters: Eugenyl and Thymyl Cinnamate Induce Cytoplasmic Vacuoles and Death in Schistosomula of Schistosoma mansoni

by Jan Glaser, Uta Schurigt, Brian M. Suzuki, Conor R. Caffrey and Ulrike Holzgrabe

Molecules 2015, 20(6), 10873-10883; https://doi.org/10.3390/molecules200610873 - 12 Jun 2015

Cited by 23 | Viewed by 7119

Abstract

Bornyl caffeate (1) was previously isolated by us from Valeriana (V.) wallichii rhizomes and identified as an anti-leishmanial substance. Here, we screened a small compound library of synthesized derivatives 1–30 for activity against schistosomula of Schistosoma (S.) mansoni. [...] Read more.

Bornyl caffeate (1) was previously isolated by us from Valeriana (V.) wallichii rhizomes and identified as an anti-leishmanial substance. Here, we screened a small compound library of synthesized derivatives 1–30 for activity against schistosomula of Schistosoma (S.) mansoni. Compound 1 did not show any anti-schistosomal activity. However, strong phenotypic changes, including the formation of vacuoles, degeneration and death were observed after in vitro treatment with compounds 23 (thymyl cinnamate) and 27 (eugenyl cinnamate). Electron microscopy analysis of the induced vacuoles in the dying parasites suggests that 23 and 27 interfere with autophagy. Full article

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Open AccessArticle

PLS-Prediction and Confirmation of Hydrojuglone Glucoside as the Antitrypanosomal Constituent of Juglans Spp.

by Therese Ellendorff, Reto Brun, Marcel Kaiser, Jandirk Sendker and Thomas J. Schmidt

Molecules 2015, 20(6), 10082-10094; https://doi.org/10.3390/molecules200610082 - 29 May 2015

Cited by 28 | Viewed by 7316

Abstract

Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found [...] Read more.

Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract’s fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol. Full article

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Open AccessArticle

Antitrypanosomal Acetylene Fatty Acid Derivatives from the Seeds of Porcelia macrocarpa (Annonaceae)

by Luciana De Á. Santos, Alberto J. Cavalheiro, Andre G. Tempone, Daniela S. Correa, Tatiana R. Alexandre, Natalia F. Quintiliano, André F. Rodrigues-Oliveira, Diogo Oliveira-Silva, Roberto Carlos C. Martins and João Henrique G. Lago

Molecules 2015, 20(5), 8168-8180; https://doi.org/10.3390/molecules20058168 - 7 May 2015

Cited by 9 | Viewed by 6604

Abstract

Chagas’ disease is caused by a parasitic protozoan and affects the poorest population in the world, causing high mortality and morbidity. As a result of the toxicity and long duration of current treatments, the discovery of novel and more efficacious drugs is crucial. [...] Read more.

Chagas’ disease is caused by a parasitic protozoan and affects the poorest population in the world, causing high mortality and morbidity. As a result of the toxicity and long duration of current treatments, the discovery of novel and more efficacious drugs is crucial. In this work, the hexane extract from seeds of Porcelia macrocarpa R.E. Fries (Annonaceae) displayed in vitro antitrypanosomal activity against trypomastigote forms of T. cruzi by the colorimetric MTT assay (IC₅₀ of 65.44 μg/mL). Using chromatographic fractionation over SiO₂, this extract afforded a fraction composed by one active compound (IC₅₀ of 10.70 µg/mL), which was chemically characterized as 12,14-octadecadiynoic acid (macrocarpic acid). Additionally, two new inactive acetylene compounds (α,α'-dimacro-carpoyl-β-oleylglycerol and α-macrocarpoyl-α'-oleylglycerol) were also isolated from the hexane extract. The complete characterization of the isolated compounds was performed by analysis of NMR and MS data as well as preparation of derivatives. Full article

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Open AccessReview

Anti-Trypanosomal Activity of Nigerian Plants and Their Constituents

by Ngozi Justina Nwodo, Akachukwu Ibezim, Fidele Ntie-Kang, Michael Umale Adikwu and Chika John Mbah

Molecules 2015, 20(5), 7750-7771; https://doi.org/10.3390/molecules20057750 - 28 Apr 2015

Cited by 55 | Viewed by 11279

Abstract

African trypanosomiasis is a vector-borne parasitic disease causing serious risks to the lives of about 60 million people and 48 million cattle globally. Nigerian medicinal plants are known to contain a large variety of chemical structures and some of the plant extracts have [...] Read more.

African trypanosomiasis is a vector-borne parasitic disease causing serious risks to the lives of about 60 million people and 48 million cattle globally. Nigerian medicinal plants are known to contain a large variety of chemical structures and some of the plant extracts have been screened for antitrypanosomal activity, in the search for potential new drugs against the illness. We surveyed the literatures on plants and plant-derived products with antitrypanosomal activity from Nigerian flora published from 1990 to 2014. About 90 plants were identified, with 54 compounds as potential active agents and presented by plant families in alphabetical order. This review indicates that the Nigerian flora may be suitable as a starting point in searching for new and more efficient trypanocidal molecules. Full article

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Open AccessArticle

Antileishmanial and Cytotoxic Compounds from Valeriana wallichii and Identification of a Novel Nepetolactone Derivative

by Jan Glaser, Martina Schultheis, Heidrun Moll, Banasri Hazra and Ulrike Holzgrabe

Molecules 2015, 20(4), 5740-5753; https://doi.org/10.3390/molecules20045740 - 1 Apr 2015

Cited by 36 | Viewed by 8691

Abstract

The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives [...] Read more.

The chloroform extract of Valeriana wallichii (V. wallichii) rhizomes was investigated to elucidate the structures responsible for reported antileishmanial activity. Besides bornyl caffeate (1, already been reported by us previously), bioassay-guided fractionation resulted in two additional cinnamic acid derivatives 2–3 with moderate leishmanicidal activity. The structure of a novel nepetolactone derivative 4 having a cinnamic acid moiety was elucidated by means of spectral analysis. To the best of our knowledge villoside aglycone (5) was isolated from this plant for the first time. The bioassay-guided fractionation yielded two new (compounds 6–7) and two known valtrates (compounds 8–9) with leishmanicidal potential against Leishmania major (L. major) promastigotes. In addition, β-bisabolol (10), α-kessyl alcohol (11), valeranone (12), bornyl isovalerate (13) and linarin-2-O-methylbutyrate (14) were identified. This is the first report on the isolation of 4'-demethylpodophyllotoxin (15), podophyllotoxin (16) and pinoresinol (17) in V. wallichii. In total thirteen known and four new compounds were identified from the extract and their cytotoxic and antileishmanial properties were evaluated. Full article

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Open AccessReview

Natural Products for the Treatment of Trachoma and Chlamydia trachomatis

by Michael G. Potroz and Nam-Joon Cho

Molecules 2015, 20(3), 4180-4203; https://doi.org/10.3390/molecules20034180 - 5 Mar 2015

Cited by 29 | Viewed by 18714

Abstract

The neglected tropical disease (NTD) trachoma is currently the leading cause of eye disease in the world, and the pathogenic bacteria causing this condition, Chlamydia trachomatis, is also the most common sexually transmitted pathogenic bacterium. Although the serovars of this bacterial species typically [...] Read more.

The neglected tropical disease (NTD) trachoma is currently the leading cause of eye disease in the world, and the pathogenic bacteria causing this condition, Chlamydia trachomatis, is also the most common sexually transmitted pathogenic bacterium. Although the serovars of this bacterial species typically vary between ocular and genital infections there is a clear connection between genital C. trachomatis infections and the development of trachoma in infants, such that the solutions to these infections are closely related. It is the unique life cycle of the C. trachomatis bacteria which primarily leads to chronic infections and challenges in treatment using conventional antibiotics. This life cycle involves stages of infective elementary bodies (EBs) and reproductive reticulate bodies (RBs). Most antibiotics only target the reproductive RBs and this often leads to the need for prolonged therapy which facilitates the development of drug resistant pathogens. It is through combining several compounds to obtain multiple antimicrobial mechanisms that we are most likely to develop a reliable means to address all these issues. Traditional and ethnobotanical medicine provides valuable resources for the development of novel formulations and treatment regimes based on synergistic and multi-compound therapy. In this review we intend to summarize the existing literature on the application of natural compounds for controlling trachoma and inhibiting chlamydial bacteria and explore the potential for the development of new treatment modalities. Full article

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Open AccessArticle

The Role of Phosphoglycans in the Susceptibility of Leishmania mexicana to the Temporin Family of Anti-Microbial Peptides

by Gabriela A. Eggimann, Kathryn Sweeney, Hannah L. Bolt, Neshat Rozatian, Steven L. Cobb and Paul W. Denny

Molecules 2015, 20(2), 2775-2785; https://doi.org/10.3390/molecules20022775 - 6 Feb 2015

Cited by 27 | Viewed by 8077

Abstract

Natural product antimicrobial peptides (AMPs) have been proposed as promising agents against the Leishmania species, insect vector borne protozoan parasites causing the neglected tropical disease leishmaniasis. However, recent studies have shown that the mammalian pathogenic amastigote form of L. mexicana, a causative [...] Read more.

Natural product antimicrobial peptides (AMPs) have been proposed as promising agents against the Leishmania species, insect vector borne protozoan parasites causing the neglected tropical disease leishmaniasis. However, recent studies have shown that the mammalian pathogenic amastigote form of L. mexicana, a causative agent of cutaneous leishmaniasis, is resistant to the amphibian-derived temporin family of AMPs when compared to the insect stage promastigote form. The mode of resistance is unknown, however the insect and mammalian stages of Leishmania possess radically different cell surface coats, with amastigotes displaying low (or zero) quantities of lipophosphoglycan (LPG) and proteophosphoglycan (PPG), macromolecules which form thick a glycocalyx in promastigotes. It has been predicted that negatively charged LPG and PPG influence the sensitivity/resistance of promastigote forms to cationic temporins. Using LPG and PPG mutant L. mexicana, and an extended range of temporins, in this study we demonstrated that whilst LPG has little role, PPG is a major factor in promastigote sensitivity to the temporin family of AMPs, possibly due to the conferred anionic charge. Therefore, the lack of PPG seen on the surface of pathogenic amastigote L. mexicana may be implicated in their resistance to these peptides. Full article

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Open AccessReview

Natural Products as Leads in Schistosome Drug Discovery

by Bruno J. Neves, Carolina H. Andrade and Pedro V. L. Cravo

Molecules 2015, 20(2), 1872-1903; https://doi.org/10.3390/molecules20021872 - 23 Jan 2015

Cited by 70 | Viewed by 11494

Abstract

Schistosomiasis is a neglected parasitic tropical disease that claims around 200,000 human lives every year. Praziquantel (PZQ), the only drug recommended by the World Health Organization for the treatment and control of human schistosomiasis, is now facing the threat of drug resistance, indicating [...] Read more.

Schistosomiasis is a neglected parasitic tropical disease that claims around 200,000 human lives every year. Praziquantel (PZQ), the only drug recommended by the World Health Organization for the treatment and control of human schistosomiasis, is now facing the threat of drug resistance, indicating the urgent need for new effective compounds to treat this disease. Therefore, globally, there is renewed interest in natural products (NPs) as a starting point for drug discovery and development for schistosomiasis. Recent advances in genomics, proteomics, bioinformatics, and cheminformatics have brought about unprecedented opportunities for the rapid and more cost-effective discovery of new bioactive compounds against neglected tropical diseases. This review highlights the main contributions that NP drug discovery and development have made in the treatment of schistosomiasis and it discusses how integration with virtual screening (VS) strategies may contribute to accelerating the development of new schistosomidal leads, especially through the identification of unexplored, biologically active chemical scaffolds and structural optimization of NPs with previously established activity. Full article

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Open AccessArticle

Insecticidal Activities of Bark, Leaf and Seed Extracts of Zanthoxylum heitzii against the African Malaria Vector Anopheles gambiae

by Hans J. Overgaard, Patcharawan Sirisopa, Bertin Mikolo, Karl E. Malterud, Helle Wangensteen, Yuan-Feng Zou, Berit S. Paulsen, Daniel Massamba, Stephane Duchon, Vincent Corbel and Fabrice Chandre

Molecules 2014, 19(12), 21276-21290; https://doi.org/10.3390/molecules191221276 - 17 Dec 2014

Cited by 18 | Viewed by 13382

Abstract

The olon tree, Zanthoxylum heitzii (syn. Fagara heitzii) is commonly found in the central-west African forests. In the Republic of Congo (Congo-Brazzaville) its bark is anecdotally reported to provide human protection against fleas. Here we assess the insecticidal activities of Z. heitzii [...] Read more.

The olon tree, Zanthoxylum heitzii (syn. Fagara heitzii) is commonly found in the central-west African forests. In the Republic of Congo (Congo-Brazzaville) its bark is anecdotally reported to provide human protection against fleas. Here we assess the insecticidal activities of Z. heitzii stem bark, seed and leaf extracts against Anopheles gambiae s.s, the main malaria vector in Africa. Extracts were obtained by Accelerated Solvent Extraction (ASE) using solvents of different polarity and by classical Soxhlet extraction using hexane as solvent. The insecticidal effects of the crude extracts were evaluated using topical applications of insecticides on mosquitoes of a susceptible reference strain (Kisumu [Kis]), a strain homozygous for the L1014F kdr mutation (kdrKis), and a strain homozygous for the G119S Ace1R allele (AcerKis). The insecticidal activities were measured using LD₅₀ and LD₉₅ and active extracts were characterized by NMR spectroscopy and HPLC chromatography. Results show that the ASE hexane stem bark extract was the most effective compound against An. gambiae (LD₅₀ = 102 ng/mg female), but was not as effective as common synthetic insecticides. Overall, there was no significant difference between the responses of the three mosquito strains to Z. heitzii extracts, indicating no cross resistance with conventional pesticides. Full article

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Open AccessArticle

Antiprotozoal Activity against Entamoeba histolytica of Plants Used in Northeast Mexican Traditional Medicine. Bioactive Compounds from Lippia graveolens and Ruta chalepensis

by Ramiro Quintanilla-Licea, Benito David Mata-Cárdenas, Javier Vargas-Villarreal, Aldo Fabio Bazaldúa-Rodríguez, Isvar Kavimngeles-Hernández, Jesús Norberto Garza-González and Magda Elizabeth Hernández-García

Molecules 2014, 19(12), 21044-21065; https://doi.org/10.3390/molecules191221044 - 15 Dec 2014

Cited by 33 | Viewed by 11928

Abstract

Amoebiasis caused by Entamoeba histolytica is associated with high morbidity and mortality is becoming a major public health problem worldwide, especially in developing countries. Because of the side-effects and the resistance that pathogenic protozoa build against the standard antiparasitic drugs, e.g., metronidazole, much [...] Read more.

Amoebiasis caused by Entamoeba histolytica is associated with high morbidity and mortality is becoming a major public health problem worldwide, especially in developing countries. Because of the side-effects and the resistance that pathogenic protozoa build against the standard antiparasitic drugs, e.g., metronidazole, much recent attention has been paid to plants used in traditional medicine around the world in order to find new antiprotozoal agents. We collected 32 plants used in Northeast Mexican traditional medicine and the methanolic extracts of these species were screened for antiprotozoal activity against E. histolytica trophozoites using in vitro tests. Only 18 extracts showed a significant inhibiting activity and among them six plant extracts showed more than 80% growth inhibition against E. histolytica at a concentration of 150 µg/mL and the IC₅₀ values of these extracts were determined. Lippia graveolens Kunth and Ruta chalepensis Pers. showed the more significant antiprotozoal activity (91.54% and 90.50% growth inhibition at a concentration of 150 µg/mL with IC₅₀ values of 59.14 and 60.07 µg/mL, respectively). Bioassay-guided fractionation of the methanolic extracts from these two plants afforded carvacrol (1) and chalepensin (2), respectively, as bioactive compounds with antiprotozoal activity. Full article

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Open AccessArticle

Preparation of Rotenone Derivatives and in Vitro Analysis of Their Antimalarial, Antileishmanial and Selective Cytotoxic Activities

by Yulieth Upegui, Juan F. Gil, Wiston Quiñones, Fernando Torres, Gustavo Escobar, Sara M. Robledo and Fernando Echeverri

Molecules 2014, 19(11), 18911-18922; https://doi.org/10.3390/molecules191118911 - 18 Nov 2014

Cited by 14 | Viewed by 7828

Abstract

Six derivatives of the known biopesticide rotenone were prepared by several chemical transformations. Rotenone and its derivatives showed differential in vitro antiparasitic activity and selective cytotoxicity. In general, compounds were more active against Plasmodium falciparum than Leishmania panamensis. Rotenone had an EC [...] Read more.

Six derivatives of the known biopesticide rotenone were prepared by several chemical transformations. Rotenone and its derivatives showed differential in vitro antiparasitic activity and selective cytotoxicity. In general, compounds were more active against Plasmodium falciparum than Leishmania panamensis. Rotenone had an EC₅₀ of 19.0 µM against P. falciparum, and 127.2 µM against L. panamensis. Although chemical transformation does not improve its biological profile against P. falciparum, three of its derivatives showed a significant level of action within an adequate range of activity with EC₅₀values < 50.0 µM. This antiplasmodial activity was not due to red blood cell hemolysis, since LC₅₀ was >>400 µM. On the other hand, all derivatives displayed a non-specific cytotoxicity on several cell lines and primary human cell cultures. Full article

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Open AccessReview

New Uses for Old Drugs: The Tale of Artemisinin Derivatives in the Elimination of Schistosomiasis Japonica in China

by Yi-Xin Liu, Wei Wu, Yue-Jin Liang, Zu-Liang Jie, Hui Wang, Wei Wang and Yi-Xin Huang

Molecules 2014, 19(9), 15058-15074; https://doi.org/10.3390/molecules190915058 - 19 Sep 2014

Cited by 49 | Viewed by 9633

Abstract

Artemisinin (qinghaosu), extracted from the Chinese herb Artemisia annua L. in 1972, and its three major derivatives—artemether, artesunate and dihydroartemisinin—were firstly identified as antimalarials and found active against all species of the malaria parasite. Since the early 1980s, artemisinin and its derivatives have [...] Read more.

Artemisinin (qinghaosu), extracted from the Chinese herb Artemisia annua L. in 1972, and its three major derivatives—artemether, artesunate and dihydroartemisinin—were firstly identified as antimalarials and found active against all species of the malaria parasite. Since the early 1980s, artemisinin and its derivatives have been found efficacious against Schistosoma spp., notably larval parasites, and artemisinin derivatives have played a critical role in the prevention and treatment of human schistosomiasis in China. Currently, China is moving towards the progress of schistosomiasis elimination. However, the potential development of praziquantel resistance may pose a great threat to the progress of elimination of schistosomiasis japonica in China. Fortunately, these three major artemisinin derivatives also exhibit actions against adult parasites, and reduced sensitivity to artemether, artesunate and dihydroartemisinin has been detected in praziquantel-resistant S. japonicum. In this review, we describe the application of artemisinin derivatives in the prevention and treatment of schistosomiasis japonica in China, so as to provide tools for the global agenda of schistosomiasis elimination. In addition to antimalarial and antischistosomal actions, they also show activities against other parasites and multiple cancers. Artemisinin derivatives, as old drugs identified firstly as antimalarials, continue to create new stories. Full article

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Open AccessReview

Hinokinin, an Emerging Bioactive Lignan

by Maria Carla Marcotullio, Azzurra Pelosi and Massimo Curini

Molecules 2014, 19(9), 14862-14878; https://doi.org/10.3390/molecules190914862 - 17 Sep 2014

Cited by 37 | Viewed by 11796

Abstract

Hinokinin is a lignan isolated from several plant species that has been recently investigated in order to establish its biological activities. So far, its cytotoxicity, its anti-inflammatory and antimicrobial activities have been studied. Particularly interesting is its notable anti-trypanosomal activity. Full article

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Open AccessArticle

The in Vitro Biological Activity of the Brazilian Brown Seaweed Dictyota mertensii against Leishmania amazonensis

by Amanda Silva dos Santos Aliança, Keicyanne Fernanda Lessa dos Anjos, Thiago Nogueira De Vasconcelos Reis, Taciana Mirely Maciel Higino, Maria Carolina Accioly Brelaz-de-Castro, Éverson Miguel Bianco and Regina Celia Bressan Queiroz De Figueiredo

Molecules 2014, 19(9), 14052-14065; https://doi.org/10.3390/molecules190914052 - 9 Sep 2014

Cited by 23 | Viewed by 9349

Abstract

Seaweeds present a wide variety of interesting bioactive molecules. In the present work we evaluated the biological activity of the dichloromethane/methanol (2:1) extract (DME) from the brown seaweed Dictyota mertensii against Leishmania amazonensis and its cytotoxic potential on mammalian cells. The extract showed [...] Read more.

Seaweeds present a wide variety of interesting bioactive molecules. In the present work we evaluated the biological activity of the dichloromethane/methanol (2:1) extract (DME) from the brown seaweed Dictyota mertensii against Leishmania amazonensis and its cytotoxic potential on mammalian cells. The extract showed significant inhibitory effect on the growth of promastigote forms (IC₅₀ = 71.60 μg/mL) and low toxicity against mammalian cells (CC₅₀ = 233.10 μg/mL). The DME was also efficient in inhibiting the infection in macrophages, with CC₅₀ of 81.4 μg/mL and significantly decreased the survival of amastigote forms within these cells. The selectivity index showed that DME was more toxic to both promastigote (SI = 3.25) and amastigote (SI = 2.86) forms than to macrophages. Increased NO production was observed in treated macrophages suggesting that besides acting directly on the parasites, the DME also shows an immunomodulatory effect on macrophages. Drastic ultrastructural alterations consistent with loss of viability and cell death were observed in treated parasites. Confocal microscopy and cytometry analyzes showed no significant impairment of plasma membrane integrity, whereas an intense depolarization of mitochondrial membrane could be observed by using propidium iodide and rhodamine 123 staining, respectively. The low toxicity to mammalian cells and the effective activity against promastigotes and amastigotes, point to the use of DME as a promising agent for the treatment of cutaneous leishmaniasis. Full article

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Open AccessArticle

In Vivo Antiplasmodial Potentials of the Combinations of Four Nigerian Antimalarial Plants

by Adeleke Clement Adebajo, Samuel Akintunde Odediran, Fatimah Abosede Aliyu, Paul Alozie Nwafor, Ndifreke Thomas Nwoko and Usenobong Samuel Umana

Molecules 2014, 19(9), 13136-13146; https://doi.org/10.3390/molecules190913136 - 26 Aug 2014

Cited by 20 | Viewed by 7096

Abstract

Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected [...] Read more.

Various combinations of Nauclea latifolia root, Artocarpus altilis stem bark, Murraya koenigii leaf and Enantia chlorantha stem bark used in African ethnomedicine as decoctions for malaria and fevers, and combinations with standard drugs, were investigated for antiplasmodial activities using Plasmodium berghei berghei-infected mice. The respective prophylactic and curative ED₅₀ values of 189.4 and 174.5 mg/kg for N. latifolia and chemosuppressive ED₅₀ value of 227.2 mg/kg for A. altilis showed that they were the best antimalarial herbal drugs. A 1.6-fold increase of the survival time given by the negative control was elicited by M. koenigii, thereby confirming its curative activity. Pyrimethamine with an ED₅₀ of 0.5 ± 0.1 mg/kg for the prophylactic, and chloroquine with ED₅₀ = 2.2 ± 0.1 and 2.2 ± 0.0 mg/kg for the chemosuppressive and curative tests, respectively, were significantly (p < 0.05) more active. Co-administrations of N. latifolia with the standard drugs significantly reduced their prophylactic, chemosuppressive and curative actions, possibly increasing the parasites’ resistance. Binary combinations of N. latifolia or M. koenigii with any of the other plants significantly increased the prophylactic and suppressive activities of their individual plants, respectively. Also, E. chlorantha with A. altilis or N. latifolia enhanced their respective prophylactic or curative activities, making these combinations most beneficial against malaria infections. Combinations of three and four extracts gave varied activities. Hence, the results justified the combinations of ethnomedicinal plants in antimalarial herbal remedies and showed the importance of the three in vivo models in establishing antimalarial activity. Full article

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Open AccessArticle

Hologram QSAR Studies of Antiprotozoal Activities of Sesquiterpene Lactones

by Gustavo H. G. Trossini, Vinícius G. Maltarollo and Thomas J. Schmidt

Molecules 2014, 19(7), 10546-10562; https://doi.org/10.3390/molecules190710546 - 18 Jul 2014

Cited by 17 | Viewed by 7575

Abstract

Infectious diseases such as trypanosomiasis and leishmaniasis are considered neglected tropical diseases due the lack for many years of research and development into new drug treatments besides the high incidence of mortality and the lack of current safe and effective drug therapies. Natural [...] Read more.

Infectious diseases such as trypanosomiasis and leishmaniasis are considered neglected tropical diseases due the lack for many years of research and development into new drug treatments besides the high incidence of mortality and the lack of current safe and effective drug therapies. Natural products such as sesquiterpene lactones have shown activity against T. brucei and L. donovani, the parasites responsible for these neglected diseases. To evaluate structure activity relationships, HQSAR models were constructed to relate a series of 40 sesquiterpene lactones (STLs) with activity against T. brucei, T. cruzi, L. donovani and P. falciparum and also with their cytotoxicity. All constructed models showed good internal (leave-one-out q² values ranging from 0.637 to 0.775) and external validation coefficients (r²_test values ranging from 0.653 to 0.944). From HQSAR contribution maps, several differences between the most and least potent compounds were found. The fragment contribution of PLS-generated models confirmed the results of previous QSAR studies that the presence of α,β-unsatured carbonyl groups is fundamental to biological activity. QSAR models for the activity of these compounds against T. cruzi, L. donovani and P. falciparum are reported here for the first time. The constructed HQSAR models are suitable to predict the activity of untested STLs. Full article

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Open AccessArticle

In Vivo Anti-Trypanosoma cruzi Activity of Hydro-Ethanolic Extract and Isolated Active Principles from Aristeguietia glutinosa and Mechanism of Action Studies

by Javier Varela, Elva Serna, Susana Torres, Gloria Yaluff, Ninfa I. Vera De Bilbao, Patricio Miño, Ximena Chiriboga, Hugo Cerecetto and Mercedes González

Molecules 2014, 19(6), 8488-8502; https://doi.org/10.3390/molecules19068488 - 23 Jun 2014

Cited by 19 | Viewed by 7834

Abstract

The currently available treatments for Chagas disease show limited therapeutic potential and are associated with serious side effects. Attempting to find alternative drugs isolated from Nature as agents against Trypanosoma cruzi has been our goal. Recently, we have demonstrated the in vitro [...] Read more.

The currently available treatments for Chagas disease show limited therapeutic potential and are associated with serious side effects. Attempting to find alternative drugs isolated from Nature as agents against Trypanosoma cruzi has been our goal. Recently, we have demonstrated the in vitro anti-T. cruzi activities of two secondary metabolites isolated from the hydro-ethanolic extract of the aerial parts of Aristeguietia glutinosa (Lam.), (family Asteraceae). These active principles displayed poor hemolytic activity, low toxicity against murine macrophages, and absence of mutagenicity. Herein, proof of concept in vivo studies of the whole hydro-ethanolic extract of the aerial parts of Aristeguietia glutinosa and of the most active component isolated from the hydro-ethanolic extract, i.e., (+)-15-hydroxy-7-labden-17-al, was done in a murine acute model of Chagas disease. Both treatments caused a decrease in the animals’ parasitemia. Metabolomic mechanism of action studies were done by ¹H-NMR, both on the extract and on the active compounds, examining the effects of the metabolites both on membrane sterol biosynthesis and mitochondrial dehydrogenases, whereby we found that one of the metabolites inhibited the activity of the parasite mitochondrial dehydrogenases and the other inhibited the biosynthesis of parasite membrane sterols. The results are interesting in the context of popular use of plants for the treatment of Chagas disease. Full article

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Open AccessArticle

Properties for Sourcing Nigerian Larvicidal Plants

by Adeleke Clement Adebajo, Funmilayo Gladys Famuyiwa and Fatima Abosede Aliyu

Molecules 2014, 19(6), 8363-8372; https://doi.org/10.3390/molecules19068363 - 19 Jun 2014

Cited by 10 | Viewed by 7956

Abstract

Aedes aegypti is the primary vector of chikungunya, yellow and dengue fevers. Dengue fever is the major cause of child morbidity and hospitalisation in some Asian and African countries, while yellow fever is prevalent in Nigeria. The development of resistance to the available [...] Read more.

Aedes aegypti is the primary vector of chikungunya, yellow and dengue fevers. Dengue fever is the major cause of child morbidity and hospitalisation in some Asian and African countries, while yellow fever is prevalent in Nigeria. The development of resistance to the available insecticides has necessitated the continued search for safer ones from plants. Eighteen plant extracts with ethnomedical claims of or demonstrated febrifuge, antimalarial, insecticidal and insect repellent biological activities were tested for activity against the fourth instar larvae of Aedes aegypti. About 61% of the eighteen extracts demonstrated high to moderate larvicidal activity. Extracts of Piper nigrum and Abrus precatorius seeds were the most active and the larvicidal constituent(s) of the latter should be determined. Full article

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Open AccessReview

Natural Products as Source of Potential Dengue Antivirals

by Róbson Ricardo Teixeira, Wagner Luiz Pereira, Ana Flávia Costa da Silveira Oliveira, Adalberto Manoel Da Silva, André Silva De Oliveira, Milene Lopes Da Silva, Cynthia Cânedo Da Silva and Sérgio Oliveira De Paula

Molecules 2014, 19(6), 8151-8176; https://doi.org/10.3390/molecules19068151 - 17 Jun 2014

Cited by 67 | Viewed by 12796

Abstract

Dengue is a neglected disease responsible for 22,000 deaths each year in areas where it is endemic. To date, there is no clinically approved dengue vaccine or antiviral for human beings, even though there have been great efforts to accomplish these goals. Several [...] Read more.

Dengue is a neglected disease responsible for 22,000 deaths each year in areas where it is endemic. To date, there is no clinically approved dengue vaccine or antiviral for human beings, even though there have been great efforts to accomplish these goals. Several approaches have been used in the search for dengue antivirals such as screening of compounds against dengue virus enzymes and structure-based computational discovery. During the last decades, researchers have turned their attention to nature, trying to identify compounds that can be used as dengue antivirals. Nature represents a vast reservoir of substances that can be explored with the aim of discovering new leads that can be either used directly as pharmaceuticals or can serve as lead structures that can be optimized towards the development of new antiviral agents against dengue. In this review we describe an assortment of natural products that have been reported as possessing dengue antiviral activity. The natural products are organized into classes of substances. When appropriate, structure-activity relationships are outlined. The biological assays used to assess antiviral activity are briefly described. Full article

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Open AccessArticle

Secondary Metabolites from Vietnamese Marine Invertebrates with Activity against Trypanosoma brucei and T. cruzi

by Nguyen Phuong Thao, Joo Hwan No, Bui Thi Thuy Luyen, Gyongseon Yang, Soo Young Byun, Junghyun Goo, Kyung Tae Kim, Nguyen Xuan Cuong, Nguyen Hoai Nam, Chau Van Minh, Thomas J. Schmidt, Jong Seong Kang and Young Ho Kim

Molecules 2014, 19(6), 7869-7880; https://doi.org/10.3390/molecules19067869 - 11 Jun 2014

Cited by 23 | Viewed by 7557

Abstract

Marine-derived natural products from invertebrates comprise an extremely diverse and promising source of the compounds from a wide variety of structural classes. This study describes the discovery of five marine natural products with activity against Trypanosoma species by natural product library screening using [...] Read more.

Marine-derived natural products from invertebrates comprise an extremely diverse and promising source of the compounds from a wide variety of structural classes. This study describes the discovery of five marine natural products with activity against Trypanosoma species by natural product library screening using whole cell in vitro assays. We investigated the anti-trypanosomal activity of the extracts from the soft corals and echinoderms living in Vietnamese seas. Of the samples screened, the methanolic extracts of several marine organisms exhibited potent activities against cultures of Trypanosoma brucei and T. cruzi (EC₅₀ < 5.0 μg/mL). Among the compounds isolated from these extracts, laevigatol B (1) from Lobophytum crassum and L. laevigatum, (24S)-ergost-4-ene-3-one (2) from Sinularia dissecta, astropectenol A (3) from Astropecten polyacanthus, and cholest-8-ene-3β,5α,6β,7α-tetraol (4) from Diadema savignyi showed inhibitory activity against T. brucei with EC₅₀ values ranging from 1.57 ± 0.14 to 14.6 ± 1.36 μM, relative to the positive control, pentamidine (EC₅₀ = 0.015 ± 0.003 μM). Laevigatol B (1) and 5α-cholest-8(14)-ene-3β,7α-diol (5) exhibited also significant inhibitory effects on T. cruzi. The cytotoxic activity of the pure compounds on mammalian cells was also assessed and found to be insignificant in all cases. This is the first report on the inhibitory effects of marine organisms collected in Vietnamese seas against Trypanosoma species responsible for neglected tropical diseases. Full article

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Open AccessArticle

Antiprotozoal Activity of Achillea ptarmica (Asteraceae) and Its Main Alkamide Constituents

by Julia B. Althaus, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2014, 19(5), 6428-6438; https://doi.org/10.3390/molecules19056428 - 20 May 2014

Cited by 39 | Viewed by 8109

Abstract

In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 [...] Read more.

In the course of our ongoing screening of plants of the family Asteraceae for antiprotozoal activity, a CH2Cl2-extract from the flowering aerial parts of Achillea ptarmica L. (sneezewort yarrow) was found to be active in vitro against Trypanosoma brucei rhodesiense (IC50 = 0.67 µg/mL) and Plasmodium falciparum (IC50 = 6.6 μg/mL). Bioassay guided fractionation led to the isolation and identification of five alkamides from the most active fractions. Pellitorine and 8,9-Z-dehyropellitorine are the main components of the extract. Beside these olefinic acid amides, four alkamides with diene-diyne structures were isolated. All alkamides were tested for antiprotozoal activity in vitro. Pellitorine was the most active compound so far within this study against P. falciparum (IC50 = 3.3 µg/mL), while 8,9-Z-dehydropellitorine was most active against T. b. rhodesiense (IC50 = 2.0 µg/mL). The activity of pure pellitorine against Plasmodium is higher than that of the crude extract and thus explains the activity of the latter. None of the isolated alkamides, however, was as active against T. b. rhodesiense as the crude extract whose antitrypanosomal activity must therfore be due to a synergistic effect of the isolated compounds or to more active yet to be identified constituents. Full article

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Open AccessArticle

Antiprotozoal Activity of Buxus sempervirens and Activity-Guided Isolation of O-tigloylcyclovirobuxeine-B as the Main Constituent Active against Plasmodium falciparum

by Julia B. Althaus, Gerold Jerz, Peter Winterhalter, Marcel Kaiser, Reto Brun and Thomas J. Schmidt

Molecules 2014, 19(5), 6184-6201; https://doi.org/10.3390/molecules19056184 - 15 May 2014

Cited by 23 | Viewed by 7721

Abstract

Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH₂Cl₂ extract from leaves of B. sempervirens showed selective in vitro activity against [...] Read more.

Buxus sempervirens L. (European Box, Buxaceae) has been used in ethnomedicine to treat malaria. In the course of our screening of plant extracts for antiprotozoal activity, a CH₂Cl₂ extract from leaves of B. sempervirens showed selective in vitro activity against Plasmodium falciparum (IC₅₀ = 2.79 vs. 20.2 µg/mL for cytotoxicity against L6 rat cells). Separation of the extract by acid/base extraction into a basic and a neutral non-polar fraction led to a much more active and even more selective fraction with alkaloids while the fraction of non-polar neutral constituents was markedly less active than the crude extract. Thus, the activity of the crude extract could clearly be attributed to alkaloid constituents. Identification of the main triterpene-alkaloids and characterization of the complex pattern of this alkaloid fraction was performed by UHPLC/+ESI-QTOF-MS analyses. ESI-MS/MS target-guided larger scale preparative separation of the alkaloid fraction was performed by ‘spiral coil-countercurrent chromatography’. From the most active subfraction, the cycloartane alkaloid O-tigloylcyclovirobuxeine-B was isolated and evaluated for antiplasmodial activity which yielded an IC₅₀ of 0.455 µg/mL (cytotoxicity against L6 rat cells: IC₅₀ = 9.38 µg/mL). O-tigloylcyclovirobuxeine-B is thus most significantly responsible for the high potency of the crude extract. Full article

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Open AccessArticle

In Vitro Leishmanicidal Activities of Sesquiterpene Lactones from Tithonia diversifolia against Leishmania braziliensis Promastigotes and Amastigotes

by Juliano S. De Toledo, Sergio R. Ambrósio, Carly H. G. Borges, Viviane Manfrim, Daniel G. Cerri, Angela K. Cruz and Fernando B. Da Costa

Molecules 2014, 19(5), 6070-6079; https://doi.org/10.3390/molecules19056070 - 14 May 2014

Cited by 34 | Viewed by 8949

Abstract

Natural compounds represent a rich and promising source of novel, biologically active chemical entities for treating leishmaniasis. Sesquiterpene lactones are a recognized class of terpenoids with a wide spectrum of biological activities, including activity against Leishmania spp. In this work, a sesquiterpene lactone-rich [...] Read more.

Natural compounds represent a rich and promising source of novel, biologically active chemical entities for treating leishmaniasis. Sesquiterpene lactones are a recognized class of terpenoids with a wide spectrum of biological activities, including activity against Leishmania spp. In this work, a sesquiterpene lactone-rich preparation—a leaf rinse extract (LRE) from Tithonia diversifolia—was tested against promastigote forms of L. braziliensis. The results revealed that the LRE is a rich source of potent leishmanicidal compounds, with an LD₅₀ value 1.5 ± 0.50 µg·mL⁻¹. Therefore, eight sesquiterpene lactones from the LRE were initially investigated against promastigote forms of L. braziliensis. One of them did not present any significant leishmanicidal effect (LD₅₀ > 50 µg·mL⁻¹). Another had a cytotoxic effect against macrophages (4.5 µg·mL⁻¹). The five leishmanicidal compounds with the highest level of selectivity were further evaluated against intracellular parasites (amastigotes) using peritoneal macrophages. Tirotundin 3-O-methyl ether, tagitinin F, and a guaianolide reduced the internalization of parasites after 48 h, in comparison with the negative control. This is the first report on sesquiterpene lactones that have potent leishmanicidal effects on both developmental stages of L. braziliensis. Full article

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Open AccessArticle

Antiparasitic Activity of Natural and Semi-Synthetic Tirucallane Triterpenoids from Schinus terebinthifolius (Anacardiaceae): Structure/Activity Relationships

by Thiago R. Morais, Thais A. Da Costa-Silva, Andre G. Tempone, Samanta Etel T. Borborema, Marcus T. Scotti, Raquel Maria F. De Sousa, Ana Carolina C. Araujo, Alberto De Oliveira, Sérgio Antônio L. De Morais, Patricia Sartorelli and João Henrique G. Lago

Molecules 2014, 19(5), 5761-5776; https://doi.org/10.3390/molecules19055761 - 5 May 2014

Cited by 38 | Viewed by 8560

Abstract

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. [...] Read more.

Leishmaniasis and Chagas are diseases caused by parasitic protozoans that affect the poorest population in the World, causing a high mortality and morbidity. As a result of highly toxic and long-term treatments, the discovery of novel, safe and more efficacious drugs is essential. In this work, the in vitro antiparasitic activity and mammalian cytotoxicity of three natural tirucallane triterpenoids, isolated from leaves of Schinus terebinthifolius (Anacardiaceae), and nine semi-synthetic derivatives were investigated against Leishmania (L.) infantum and Trypanosoma cruzi. Trypomastigotes of T. cruzi were the most susceptible parasites and seven compounds demonstrated a trypanocidal activity with IC₅₀ values in the range between 15 and 58 µg/mL. Four compounds demonstrated selectivity towards the intracellular amastigotes of Leishmania, with IC₅₀ values in the range between 28 and 97 µg/mL. The complete characterization of triterpenoids was afforded after thorough analysis of nuclear magnetic resonance (NMR) data as well as electrospray ionization mass spectrometry (ESI-MS). Additionally, structure-activity relationships were performed using Decision Trees. Full article

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Open AccessArticle

Leishmanicidal Evaluation of Tetrahydroprotoberberine and Spirocyclic Erythrina-Alkaloids

by Daniel R. Callejon, Thalita B. Riul, Luis G. P. Feitosa, Thais Guaratini, Denise B. Silva, Achyut Adhikari, Ram L. Shrestha, Lucas M. M. Marques, Marcelo D. Baruffi, João L. C. Lopes and Norberto P. Lopes

Molecules 2014, 19(5), 5692-5703; https://doi.org/10.3390/molecules19055692 - 5 May 2014

Cited by 38 | Viewed by 8883

Abstract

Leishmaniasis is one of the World’s most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and [...] Read more.

Leishmaniasis is one of the World’s most problematic diseases in developing countries. Traditional medicines to treat leishmaniasis have serious side effects, as well as significant parasite resistance problems. In this work, two alkaloids 1 and 2 were obtained from Corydalis govaniana Wall and seven alkaloids 3–9, were obtained from Erythrina verna. The structures of the compounds were confirmed by mass spectrometry and 1D- and 2D-NMR spectroscopy. The leishmanicidal activity of compounds 1–9 against Leishmania amazonensis was tested on promastigote forms and cytotoxicity against J774 (macrophage cell line) was assessed in vitro. Compound 1 showed potent activity (IC₅₀ = 0.18 µg/mL), compared with the standard amphotericin B (IC₅₀ = 0.20 µg/mL). The spirocyclic erythrina-alkaloids showed lower leishmanicidal activity than dibenzoquinolizine type alkaloids. Full article

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Open AccessArticle

In-Silico Analyses of Sesquiterpene-Related Compounds on Selected Leishmania Enzyme-Based Targets

by Freddy A. Bernal and Ericsson Coy-Barrera

Molecules 2014, 19(5), 5550-5569; https://doi.org/10.3390/molecules19055550 - 29 Apr 2014

Cited by 31 | Viewed by 8868

Abstract

A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve [...] Read more.

A great number of sesquiterpenes are reported in the available literature as good antileishmanial leads. However, their mode of action at the molecular level has not been elucidated. The lack of molecular studies could be considered an impediment for studies seeking to improve sesquiterpene-based drug design. The present in silico study allows us to make important observations about the molecular details of the binding modes of a set of antileishmanial sesquiterpenes against four drug-enzyme targets [pteridine reductase-1 (PTR1), N-myristoyl transferase (NMT), cysteine synthase (CS), trypanothione synthetase (TryS)]. Through molecular docking it was found that two sesquiterpene coumarins are promising leads for the PTR1 and TryS inhibition purposes, and some xanthanolides also exhibited better affinity towards PTR1 and CS binding. In addition, the affinity values were clustered by Principal Component Analysis and drug-like properties were analyzed for the strongest-docking sesquiterpenes. The results are an excellent starting point for future studies of structural optimization of this kind of compounds. Full article

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Open AccessArticle

Two Trypanocidal Dipeptides from the Roots of Zapoteca portoricensis (Fabaceae)

by Ngozi Justina Nwodo, Festus Basden C. Okoye, Daowan Lai, Abdessamad Debbab, Reto Brun and Peter Proksch

Molecules 2014, 19(5), 5470-5477; https://doi.org/10.3390/molecules19055470 - 25 Apr 2014

Cited by 26 | Viewed by 7612

Abstract

Zapoteca portoricensis (Jacq) HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) [...] Read more.

Zapoteca portoricensis (Jacq) HM Hernández is used with remarkable efficacy in ethnomedicinal management of tonsillitis in the Eastern part of Nigeria. Previous pharmacological studies have validated the antiinflammatory and antimicrobial activities of the crude extract. In this study, two dipeptides, saropeptate (aurantiamide acetate) and anabellamide, were isolated from the methanol root extract of Zapoteca portoricensis and their chemical structures deduced by one dimensional and two dimensional NMR and mass spectrometry. These compounds were isolated for the first time from this plant, and no report has been found on their previous isolation from the genus Zapoteca. Evaluation of their trypanocidal activity showed that compound 1 exhibited potent activity against Trypanosoma brucei rhodesiense with an IC50 value of 3.63 μM and selectivity index of 25.3. Full article

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Open AccessArticle

A Benzoic Acid Derivative and Flavokawains from Piper species as Schistosomiasis Vector Controls

by Ludmila N. Rapado, Giovana C. Freitas, Adriano Polpo, Maritza Rojas-Cardozo, Javier V. Rincón, Marcus T. Scotti, Massuo J. Kato, Eliana Nakano and Lydia F. Yamaguchi

Molecules 2014, 19(4), 5205-5218; https://doi.org/10.3390/molecules19045205 - 23 Apr 2014

Cited by 11 | Viewed by 7383

Abstract

The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic [...] Read more.

The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic acid derivative and three flavokawains from Piper diospyrifolium, P. cumanense and P. gaudichaudianum displayed significant activities against Biomphalaria glabrata snails. Additionally, “in silico” studies were performed using docking assays and Molecular Interaction Fields to evaluate the physical-chemical differences among the compounds in order to characterize the observed activities of the test compounds against Biomphalaria glabrata snails. Full article

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Open AccessArticle

Antiprotozoal Activities of Millettia richardiana (Fabaceae) from Madagascar

by Manitriniaina Rajemiarimiraho, Jean-Théophile Banzouzi, Marie-Laure Nicolau-Travers, Suzanne Ramos, Zakaria Cheikh-Ali, Christian Bories, Olga L. Rakotonandrasana, Stéphane Rakotonandrasana, Philippe Antoine Andrianary and Françoise Benoit-Vical

Molecules 2014, 19(4), 4200-4211; https://doi.org/10.3390/molecules19044200 - 3 Apr 2014

Cited by 7 | Viewed by 7252

Abstract

With at least 60% of the Millettia species (Fabaceae) being in medicinal use, we found it relevant to assess the potential antiprotozoal and antifungal activities of Millettia richardiana. Water and methanol crude extracts of the stem barks from M. richardiana and the six [...] Read more.

With at least 60% of the Millettia species (Fabaceae) being in medicinal use, we found it relevant to assess the potential antiprotozoal and antifungal activities of Millettia richardiana. Water and methanol crude extracts of the stem barks from M. richardiana and the six fractions resulting from the fractionation of the methanol extract were tested. The dichloromethane extracted fraction showed the best in vitro antiprotozoal activities (IC₅₀ = 5.8 μg/mL against Plasmodium falciparum, 11.8 μg/mL against Leishmania donovani and 12.8 μg/mL against Trypanosoma brucei brucei) as well as low cytotoxicity on several cell lines. The phytochemical analysis showed this selected fraction to be rich in terpenoids and alkaloids, which could explain its antiparasitic activity. A phytochemical study revealed the presence of lonchocarpenin, betulinic acid, β-amyrin, lupeol, palmitic acid, linoleic acid and stearic acid, among which betulinic acid and lupeol could be the compounds responsible of these antiprotozoal activities. By contrast, neither the crude extracts nor the fractions showed antifungal activity against Candida. These results confirm the importance of the genus Millettia in Malagasy ethnomedicine, its potential use in antiparasitic therapy, and the interest of developing a sustainable exploitation of this plant. Moreover, both molecules betulinic acid and lupeol appeared as very relevant molecules for their antiprotozoal properties. Full article

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Open AccessArticle

Antischistosomal Activity of the Terpene Nerolidol

by Marcos P.N. Silva, George L.S. Oliveira, Rusbene B.F. De Carvalho, Damião P. De Sousa, Rivelilson M. Freitas, Pedro L.S. Pinto and Josué De Moraes

Molecules 2014, 19(3), 3793-3803; https://doi.org/10.3390/molecules19033793 - 24 Mar 2014

Cited by 54 | Viewed by 8824

Abstract

Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people worldwide. Since the treatment of this disease currently relies on a single drug, praziquantel, new and safe schistosomicidal agents are urgently required. Nerolidol, a sesquiterpene present in the essential oils [...] Read more.

Schistosomiasis is a neglected tropical disease that affects hundreds of millions of people worldwide. Since the treatment of this disease currently relies on a single drug, praziquantel, new and safe schistosomicidal agents are urgently required. Nerolidol, a sesquiterpene present in the essential oils of several plants, is found in many foods and was approved by the U.S. Food and Drug Administration. In this study we analysed the in vitro antiparasitic effect of nerolidol on Schistosoma mansoni adult worms. Nerolidol at concentrations of 31.2 and 62.5 μM reduced the worm motor activity and caused the death of all male and female schistosomes, respectively. In addition, confocal laser scanning microscopy revealed morphological alterations on the tegument of worms such as disintegration, sloughing and erosion of the surface, and a correlation between viability and tegumental damage was observed. In conclusion, nerolidol may be a promising lead compound for the development of antischistosomal natural agents. Full article

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Open AccessArticle

Structure-Activity Relationship Study of Sesquiterpene Lactones and Their Semi-Synthetic Amino Derivatives as Potential Antitrypanosomal Products

by Stefanie Zimmermann, Gerda Fouché, Maria De Mieri, Yukiko Yoshimoto, Toyonobu Usuki, Rudzani Nthambeleni, Christopher J. Parkinson, Christiaan Van der Westhuyzen, Marcel Kaiser, Matthias Hamburger and Michael Adams

Molecules 2014, 19(3), 3523-3538; https://doi.org/10.3390/molecules19033523 - 21 Mar 2014

Cited by 35 | Viewed by 9340

Abstract

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and [...] Read more.

Sesquiterpene lactones (STLs) are natural products that have potent antitrypanosomal activity in vitro and, in the case of cynaropicrin, also reduce parasitemia in the murine model of trypanosomiasis. To explore their structure-antitrypanosomal activity relationships, a set of 34 natural and semi-synthetic STLs and amino-STLs was tested in vitro against T. b. rhodesiense (which causes East African sleeping sickness) and mammalian cancer cells (rat bone myoblast L6 cells). It was found that the α-methylene-γ-lactone moiety is necessary for both antitrypanosomal effects and cytotoxicity. Antitrypanosomal selectivity is facilitated by 2-(hydroxymethyl)acrylate or 3,4-dihydroxy-2-methylenebutylate side chains, and by the presence of cyclopentenone rings. Semi-synthetic STL amines with morpholino and dimethylamino groups showed improved in vitro activity over the native STLs. The dimethylamino derivative of cynaropicrin was prepared and tested orally in the T. b. rhodesiense acute mouse model, where it showed reduced toxicity over cynaropicrin, but also lost antitrypanosomal activity. Full article

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Open AccessArticle

Synthetic Fosmidomycin Analogues with Altered Chelating Moieties Do Not Inhibit 1-Deoxy-D-xylulose 5-phosphate Reductoisomerase or Plasmodium falciparum Growth In Vitro

by René Chofor, Martijn D.P. Risseeuw, Jenny Pouyez, Chinchu Johny, Johan Wouters, Cynthia S. Dowd, Robin D. Couch and Serge Van Calenbergh

Molecules 2014, 19(2), 2571-2587; https://doi.org/10.3390/molecules19022571 - 24 Feb 2014

Cited by 15 | Viewed by 8122

Abstract

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or [...] Read more.

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or the Plasmodia. This study further underlines the importance of the hydroxamate functionality and illustrates that identifying effective alternative bidentate ligands for this target enzyme is challenging. Full article

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Open AccessArticle

Antileishmanial Lead Structures from Nature: Analysis of Structure-Activity Relationships of a Compound Library Derived from Caffeic Acid Bornyl Ester

by Jan Glaser, Martina Schultheis, Sudipta Hazra, Banasri Hazra, Heidrun Moll, Uta Schurigt and Ulrike Holzgrabe

Molecules 2014, 19(2), 1394-1410; https://doi.org/10.3390/molecules19021394 - 27 Jan 2014

Cited by 31 | Viewed by 9473

Abstract

Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC [...] Read more.

Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC₅₀ = 48.8 µM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization. Full article

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