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1461 KiB

Open AccessArticle

Design, Synthesis, and Fungicidal Activity of Novel Thiosemicarbazide Derivatives Containing Piperidine Fragments

by Xuebo Zhang, Peng Lei, Tengda Sun, Xiaoyu Jin, Xinling Yang and Yun Ling

Molecules 2017, 22(12), 2085; https://doi.org/10.3390/molecules22122085 - 11 Dec 2017

Cited by 29 | Viewed by 6268

Abstract

In order to discover novel eco-friendly lead compounds for plant pathogenic fungi control, a series of benzaldehyde thiosemicarbazide derivatives with a piperidine moiety have been designed and synthesized. Fungicidal activities of all the synthesized compounds were evaluated in vitro. The results indicated that [...] Read more.

In order to discover novel eco-friendly lead compounds for plant pathogenic fungi control, a series of benzaldehyde thiosemicarbazide derivatives with a piperidine moiety have been designed and synthesized. Fungicidal activities of all the synthesized compounds were evaluated in vitro. The results indicated that all the title compounds exhibited moderate to good fungicidal activities. Compound 3b displayed excellent activities against Pythium aphanidermatum, Rhizoctonia solani, Valsa mali, and Gaeu-mannomyces graminsis, with EC₅₀ values lower than 10 μg/mL. Especially, in the case of Pythium aphanidermatum, its activity (EC₅₀ = 1.6 μg/mL) is superior to the commercial azoxystrobin (EC₅₀ = 16.9 μg/mL) and close to fluopicolide (EC₅₀ = 1.0 μg/mL). Initial structure–activity relationship (SAR) analysis showed that the heterocyclic piperidine group can influence the biological activities of the title compounds significantly. The fungicidal activity of compounds with piperidine is better than that of compounds without piperidine. The highly-active compound 3b, with its simple structure and easy synthetic route, is worthy to be further studied as a new lead fungicide. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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571 KiB

Open AccessCommunication

Novel Effective Small-Molecule Antibacterials against Enterococcus Strains

by Kerolos Ashraf, Kaveh Yasrebi, Tobias Hertlein, Knut Ohlsen, Michael Lalk and Andreas Hilgeroth

Molecules 2017, 22(12), 2193; https://doi.org/10.3390/molecules22122193 - 10 Dec 2017

Cited by 2 | Viewed by 4447

Abstract

Enterococcus species cause increasing numbers of infections in hospitals. They contribute to the increasing mortality rates, mostly in patients with comorbidities, who suffer from severe diseases. Enterococcus resistances against most antibiotics have been described, including novel antibiotics. Therefore, there is an ongoing demand [...] Read more.

Enterococcus species cause increasing numbers of infections in hospitals. They contribute to the increasing mortality rates, mostly in patients with comorbidities, who suffer from severe diseases. Enterococcus resistances against most antibiotics have been described, including novel antibiotics. Therefore, there is an ongoing demand for novel types of antibiotics that may overcome bacterial resistances. We discovered a novel class of antibiotics resulting from a simple one-pot reaction of indole and o-phthaldialdehyde. Differently substituted indolyl benzocarbazoles were yielded. Both the indole substitution and the positioning at the molecular scaffold influence the antibacterial activity towards the various strains of Enterococcus species with the highest relevance to nosocomial infections. Structure-activity relationships are discussed, and the first lead compounds were identified as also being effective in the case of a vancomycin resistance. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1068 KiB

Open AccessArticle

Synthesis and Antibacterial Evaluation of a Series of 11,12-Cyclic Carbonate Azithromycin-3-O-descladinosyl-3-O-carbamoyl Glycosyl Derivatives

by Chao-Ming Wang, Feng-Lan Zhao, Lei Zhang, Xiao-Yun Chai and Qing-Guo Meng

Molecules 2017, 22(12), 2146; https://doi.org/10.3390/molecules22122146 - 4 Dec 2017

Cited by 4 | Viewed by 4383

Abstract

A novel series of 11,12-cyclic carbonate azithromycin-3-O-descladinosyl-3-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against seven kinds of susceptible strains. In particular, compound G1 exhibited [...] Read more.

A novel series of 11,12-cyclic carbonate azithromycin-3-O-descladinosyl-3-O-carbamoyl glycosyl derivatives were designed, synthesized, and evaluated for their antibacterial activities in vitro. Most of these compounds had significant antibacterial activity against seven kinds of susceptible strains. In particular, compound G1 exhibited the most potent activity against methicillin-resistant Streptococcus pneumoniae 943 (MIC: 1 μg/mL), Staphylococcus pneumoniae 746 (MIC: 2 μg/mL), Streptococcus pyogenes 447 (MIC: 8 μg/mL), and Escherichia coli 236 (MIC: 32 μg/mL), which were two-, four-, four-, four-, and eight-fold stronger activity than azithromycin, respectively. Additionally, compound G2 exhibited improved activity against methicillin-resistant Staphylococcus aureus MRSA-1 (MIC: 8 μg/mL), Streptococcus pneumoniae 943 (MIC: 2 μg/mL), Staphylococcus pneumoniae 746 (MIC: 2 μg/mL), and Escherichia coli 236 (MIC: 32 μg/mL), which were two-, two-, four-, and eight-fold better activity than azithromycin, respectively. As for methicillin-resistant Staphylococcus aureus MRSA-1, compound G6 presented the most excellent activity (MIC: 4 μg/mL), showing four-fold higher activity than azithromycin (MIC: 16 μg/mL) and erythromycin (MIC: 16 μg/mL). However, compared with other compounds, compounds G7 and G8 with the disaccharide side chain were observed the lower activity against seven strains. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1785 KiB

Open AccessArticle

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain

by Tomáš Goněc, Ivan Malík, Jozef Csöllei, Josef Jampílek, Jiřina Stolaříková, Ivan Solovič, Peter Mikuš, Stanislava Keltošová, Peter Kollár, Jim O’Mahony and Aidan Coffey

Molecules 2017, 22(12), 2100; https://doi.org/10.3390/molecules22122100 - 30 Nov 2017

Cited by 12 | Viewed by 5186

Abstract

Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a–h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water [...] Read more.

Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a–h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log k_w values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕ_M), varied from 2.113 (compound 8e) to 2.930 (8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a–h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a–h were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H₃₇R_v and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8a–h were found to be the most promising against M. tuberculosis; a MIC = 8 μM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD₅₀ values > 30 μM indicated. The structure–antimycobacterial activity relationships of the analyzed 8a–h series are also discussed. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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5945 KiB

Open AccessArticle

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies

by Alejandra Vázquez-Raygoza, Lucia Cano-González, Israel Velázquez-Martínez, Pedro Josué Trejo-Soto, Rafael Castillo, Alicia Hernández-Campos, Francisco Hernández-Luis, Jesús Oria-Hernández, Adriana Castillo-Villanueva, Claudia Avitia-Domínguez, Erick Sierra-Campos, Mónica Valdez-Solana and Alfredo Téllez-Valencia

Molecules 2017, 22(12), 2055; https://doi.org/10.3390/molecules22122055 - 24 Nov 2017

Cited by 14 | Viewed by 5634

Abstract

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find [...] Read more.

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei. Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1, 2 and 3) with an I₅₀ value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1038 KiB

Open AccessArticle

Synthesis and Anticandidal Activity Evaluation of New Benzimidazole-Thiazole Derivatives

by Zafer Asım Kaplancıklı, Serkan Levent, Derya Osmaniye, Begüm Nurpelin Sağlık, Ulviye Acar Çevik, Betül Kaya Çavuşoğlu, Yusuf Özkay and Sinem Ilgın

Molecules 2017, 22(12), 2051; https://doi.org/10.3390/molecules22122051 - 23 Nov 2017

Cited by 21 | Viewed by 5719

Abstract

Azole-based antifungal agents constitute one of the important classes of antifungal drugs. Hence, in the present work, 12 new benzimidazole-thiazole derivatives 3a–3l were synthesized to evaluate their anticandidal activity against C. albicans, C. glabrata, C. krusei, and C. [...] Read more.

Azole-based antifungal agents constitute one of the important classes of antifungal drugs. Hence, in the present work, 12 new benzimidazole-thiazole derivatives 3a–3l were synthesized to evaluate their anticandidal activity against C. albicans, C. glabrata, C. krusei, and C. parapsilopsis. The structures of the newly synthesized compounds 3a–3l were confirmed by IR, ¹H-NMR, ¹³C-NMR, and ESI-MS spectroscopic methods. ADME parameters of synthesized compounds 3a–3l were predicted by an in-slico study and it was determined that all synthesized compounds may have a good pharmacokinetic profile. In the anticandidal activity studies, compounds 3c and 3d were found to be the most active compounds against all Candida species. In addition, cytoxicity studies showed that these compounds are nontoxic with a IC₅₀ value higher than 500 µg/mL. The effect of compounds 3c and 3d on the ergosterol level of C. albicans was determined by an LC-MS-MS method. It was observed that both compounds cause a decrease in the ergosterol level. A molecular docking study including binding modes of 3c to lanosterol 14α-demethylase (CYP51), a key enzyme in ergosterol biosynthesis, was performed to elucidate the mechanism of the antifungal action. The docking studies revealed that there is a strong interaction between CYP51 and the most active compound 3c. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1326 KiB

Open AccessArticle

Synthesis of Oxadiazole-Thiadiazole Hybrids and Their Anticandidal Activity

by Serkan Levent, Betül Kaya Çavuşoğlu, Begüm Nurpelin Sağlık, Derya Osmaniye, Ulviye Acar Çevik, Özlem Atlı, Yusuf Özkay and Zafer Asım Kaplancıklı

Molecules 2017, 22(11), 2004; https://doi.org/10.3390/molecules22112004 - 18 Nov 2017

Cited by 18 | Viewed by 4126

Abstract

In the field of infection management, it is a major challenge to discover a potent and safe antifungal agent due to the emergence of resistant strains. Hence, the goal of this paper is to design and synthesize novel oxadiazole-thiadiazole hybrid compounds (6a [...] Read more.

In the field of infection management, it is a major challenge to discover a potent and safe antifungal agent due to the emergence of resistant strains. Hence, the goal of this paper is to design and synthesize novel oxadiazole-thiadiazole hybrid compounds (6a–6s) and evaluate their antifungal activity. The structures of synthesized compounds were elucidated by various methods including FT-IR, ¹H-NMR, ¹³C-NMR and HR-MS spectral data. Compounds were tested against four Candida species by broth microdilution assay. Compounds 6e, 6k and 6r, bearing a nitro group, showed significant antifungal activity against all fungi with minimum inhibitory concentration (MIC) in the range of 0.78–3.12 µg/mL. These compounds were also screened for their in vitro cytotoxic effects by MTT assay and detected as nontoxic at their active concentrations against Candida strains. To examine the effects of these compounds on ergosterol biosynthesis, the LC-MS-MS method, which is based on quantification of ergosterol level in C. krusei, was carried out. Finally, the most active molecule (6e) was docked in the active site of the lanosterol 14α-demethylase enzyme, and it was determined that there is a strong interaction between the compound and enzyme. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1108 KiB

Open AccessArticle

Synthesis, Single Crystal X-ray Analysis, and Antifungal Profiling of Certain New Oximino Ethers Bearing Imidazole Nuclei

by Reem I. Al-Wabli, Alwah R. Al-Ghamdi, Hazem A. Ghabbour, Mohamed H. Al-Agamy and Mohamed I. Attia

Molecules 2017, 22(11), 1895; https://doi.org/10.3390/molecules22111895 - 3 Nov 2017

Cited by 4 | Viewed by 3834

Abstract

Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically [...] Read more.

Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers Va–n bearing imidazole nuclei are reported. The (E)-configuration of the imine double bond of the synthesized compounds Va–n has been confirmed via single crystal X-ray analysis of compound Vi as a representative example of this class of compounds. The molecular structure of compound Vi was crystallized in the monoclinic, P2₁/c, a = 18.7879(14) Å, b = 5.8944(4) Å, c = 16.7621(12) Å, β = 93.063(3)°, V = 1855.5(2) Å³, Z = 4. The in vitro antifungal activity of the synthesized compounds Va–n were evaluated using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against different fungal strains. Compound Ve manifested anti-Candida albicans activity with an MIC value of 0.050 µmol/mL, being almost equipotent with the reference antifungal drug fluconazole (FLC),while compounds Vi and Vn are the most active congeners against Candida parapsilosis, being equipotent and about twenty-three times more potent than FLC with an MIC value of 0.002 µmol/mL. The results of the current report might support the development of new potent and safer antifungal azoles. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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793 KiB

Open AccessArticle

Novel Triazole Hybrids of Betulin: Synthesis and Biological Activity Profile

by Ewa Bębenek, Maria Jastrzębska, Monika Kadela-Tomanek, Elwira Chrobak, Beata Orzechowska, Katarzyna Zwolińska, Małgorzata Latocha, Anna Mertas, Zenon Czuba and Stanisław Boryczka

Molecules 2017, 22(11), 1876; https://doi.org/10.3390/molecules22111876 - 1 Nov 2017

Cited by 56 | Viewed by 5761

Abstract

Betulin derivatives containing a 1,2,3-triazole ring possess a wide spectrum of biological activities, including antiviral, anticancer, and antibacterial activity. A series of novel triazoles were prepared by the 1,3-dipolar cycloaddition reaction between the alkyne derivatives of betulin and organic azides. The chemical structures [...] Read more.

Betulin derivatives containing a 1,2,3-triazole ring possess a wide spectrum of biological activities, including antiviral, anticancer, and antibacterial activity. A series of novel triazoles were prepared by the 1,3-dipolar cycloaddition reaction between the alkyne derivatives of betulin and organic azides. The chemical structures of the obtained compounds were defined by ¹H and ¹³C NMR, IR, and high-resolution mass spectrometry (HR-MS) analysis. The target triazoles were screened for their antiviral activity against DNA and RNA viruses. The cytotoxic activity of the obtained compounds 5a–k and 6a–h was determined using five human cancer cell lines (T47D, MCF-7, SNB-19, Colo-829, and C-32) by a WST-1 assay. The bistriazole 6b displayed a promising IC₅₀ value (0.05 μM) against the human ductal carcinoma T47D (500-fold higher potency than cisplatin). The microdilution method was applied for an evaluation of the antimicrobial activity of all of the compounds. The triazole 5e containing a 3′-deoxythymidine-5′-yl moiety exhibited antibacterial activity against two gram-negative bacteria vz. Klebsiella pneumoniae and Escherichia coli (minimal inhibitory concentration (MIC) range of 0.95–1.95 μM). Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1301 KiB

Open AccessArticle

Synthesis and Biological Evaluation of 2H-Indazole Derivatives: Towards Antimicrobial and Anti-Inflammatory Dual Agents

by Jaime Pérez-Villanueva, Lilián Yépez-Mulia, Ignacio González-Sánchez, Juan Francisco Palacios-Espinosa, Olivia Soria-Arteche, Teresita Del Rosario Sainz-Espuñes, Marco A. Cerbón, Karen Rodríguez-Villar, Ana Karina Rodríguez-Vicente, Miguel Cortés-Gines, Zeltzin Custodio-Galván and Dante B. Estrada-Castro

Molecules 2017, 22(11), 1864; https://doi.org/10.3390/molecules22111864 - 31 Oct 2017

Cited by 39 | Viewed by 6972

Abstract

Indazole is considered a very important scaffold in medicinal chemistry. It is commonly found in compounds with diverse biological activities, e.g., antimicrobial and anti-inflammatory agents. Considering that infectious diseases are associated to an inflammatory response, we designed a set of 2H-indazole [...] Read more.

Indazole is considered a very important scaffold in medicinal chemistry. It is commonly found in compounds with diverse biological activities, e.g., antimicrobial and anti-inflammatory agents. Considering that infectious diseases are associated to an inflammatory response, we designed a set of 2H-indazole derivatives by hybridization of cyclic systems commonly found in antimicrobial and anti-inflammatory compounds. The derivatives were synthesized and tested against selected intestinal and vaginal pathogens, including the protozoa Giardia intestinalis, Entamoeba histolytica, and Trichomonas vaginalis; the bacteria Escherichia coli and Salmonella enterica serovar Typhi; and the yeasts Candida albicans and Candida glabrata. Biological evaluations revealed that synthesized compounds have antiprotozoal activity and, in most cases, are more potent than the reference drug metronidazole, e.g., compound 18 is 12.8 times more active than metronidazole against G. intestinalis. Furthermore, two 2,3-diphenyl-2H-indazole derivatives (18 and 23) showed in vitro growth inhibition against Candida albicans and Candida glabrata. In addition to their antimicrobial activity, the anti-inflammatory potential for selected compounds was evaluated in silico and in vitro against human cyclooxygenase-2 (COX-2). The results showed that compounds 18, 21, 23, and 26 display in vitro inhibitory activity against COX-2, whereas docking calculations suggest a similar binding mode as compared to rofecoxib, the crystallographic reference. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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4365 KiB

Open AccessArticle

Benzoic Acid Derivatives with Trypanocidal Activity: Enzymatic Analysis and Molecular Docking Studies toward Trans-Sialidase

by Muhammad Kashif, Antonio Moreno-Herrera, Juan Carlos Villalobos-Rocha, Benjamín Nogueda-Torres, Jaime Pérez-Villanueva, Karen Rodríguez-Villar, José Lius Medina-Franco, Peterson De Andrade, Ivone Carvalho and Gildardo Rivera

Molecules 2017, 22(11), 1863; https://doi.org/10.3390/molecules22111863 - 30 Oct 2017

Cited by 16 | Viewed by 7482

Abstract

Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic [...] Read more.

Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as trans-sialidase (TS) inhibitors and anti-trypanosomal agents. Three compounds (14, 18, and 19) sharing a para-aminobenzoic acid moiety showed more potent trypanocidal activity than the commercially available drugs nifurtimox and benznidazole in both strains: the lysis concentration of 50% of the population (LC₅₀) was <0.15 µM on the NINOA strain, and LC₅₀ < 0.22 µM on the INC-5 strain. Additionally, compound 18 showed a moderate inhibition (47%) on the trans-sialidase enzyme and a binding model similar to DANA (pattern A). Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1923 KiB

Open AccessArticle

Screening a Natural Product-Based Library against Kinetoplastid Parasites

by Bilal Zulfiqar, Amy J. Jones, Melissa L. Sykes, Todd B. Shelper, Rohan A. Davis and Vicky M. Avery

Molecules 2017, 22(10), 1715; https://doi.org/10.3390/molecules22101715 - 12 Oct 2017

Cited by 48 | Viewed by 8235

Abstract

Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the [...] Read more.

Kinetoplastid parasites cause vector-borne parasitic diseases including leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease. These Neglected Tropical Diseases (NTDs) impact on some of the world’s lowest socioeconomic communities. Current treatments for these diseases cause severe toxicity and have limited efficacy, highlighting the need to identify new treatments. In this study, the Davis open access natural product-based library was screened against kinetoplastids (Leishmania donovani DD8, Trypanosoma brucei brucei and Trypanosoma cruzi) using phenotypic assays. The aim of this study was to identify hit compounds, with a focus on improved efficacy, selectivity and potential to target several kinetoplastid parasites. The IC₅₀ values of the natural products were obtained for L. donovani DD8, T. b. brucei and T. cruzi in addition to cytotoxicity against the mammalian cell lines, HEK-293, 3T3 and THP-1 cell lines were determined to ascertain parasite selectivity. Thirty-one compounds were identified with IC₅₀ values of ≤ 10 µM against the kinetoplastid parasites tested. Lissoclinotoxin E (1) was the only compound identified with activity across all three investigated parasites, exhibiting IC₅₀ values < 5 µM. In this study, natural products with the potential to be new chemical starting points for drug discovery efforts for kinetoplastid diseases were identified. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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2150 KiB

Open AccessArticle

Nano-Formulation of Ethambutol with Multifunctional Graphene Oxide and Magnetic Nanoparticles Retains Its Anti-Tubercular Activity with Prospects of Improving Chemotherapeutic Efficacy

by Bullo Saifullah, Arundhati Maitra, Alina Chrzastek, Bullo Naeemullah, Sharida Fakurazi, Sanjib Bhakta and Mohd Zobir Hussein

Molecules 2017, 22(10), 1697; https://doi.org/10.3390/molecules22101697 - 12 Oct 2017

Cited by 22 | Viewed by 6419

Abstract

Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization’s recommended frontline chemotherapy against TB. However, the lengthy [...] Read more.

Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization’s recommended frontline chemotherapy against TB. However, the lengthy treatment regimens consisting of a cocktail of antibiotics affect patient compliance. There is an urgent need to improve the current therapy so as to reduce treatment duration and dosing frequency. In this study, we have designed a novel anti-TB multifunctional formulation by fabricating graphene oxide with iron oxide magnetite nanoparticles serving as a nano-carrier on to which ethambutol was successfully loaded. The designed nanoformulation was characterised using various analytical techniques. The release of ethambutol from anti-TB multifunctional nanoparticles formulation was found to be sustained over a significantly longer period of time in phosphate buffer saline solution at two physiological pH (7.4 and 4.8). Furthermore, the nano-formulation showed potent anti-tubercular activity while remaining non-toxic to the eukaryotic cells tested. The results of this in vitro evaluation of the newly designed nano-formulation endorse its further development in vivo. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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944 KiB

Open AccessArticle

Antibacterial and Antitubercular Activities of Cinnamylideneacetophenones

by Carlos R. Polaquini, Guilherme S. Torrezan, Vanessa R. Santos, Ana C. Nazaré, Débora L. Campos, Laíza A. Almeida, Isabel C. Silva, Henrique Ferreira, Fernando R. Pavan, Cristiane Duque and Luis O. Regasini

Molecules 2017, 22(10), 1685; https://doi.org/10.3390/molecules22101685 - 10 Oct 2017

Cited by 22 | Viewed by 6878

Abstract

Cinnamaldehyde is a natural product with broad spectrum of antibacterial activity. In this work, it was used as a template for design and synthesis of a series of 17 cinnamylideneacetophenones. Phenolic compounds 3 and 4 exhibited MIC (minimum inhibitory concentration) and MBC (minimum [...] Read more.

Cinnamaldehyde is a natural product with broad spectrum of antibacterial activity. In this work, it was used as a template for design and synthesis of a series of 17 cinnamylideneacetophenones. Phenolic compounds 3 and 4 exhibited MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration) values of 77.9 to 312 µM against Staphylococcus aureus, Streptococcus mutans, and Streptococcus sanguinis. Compounds 2, 7, 10, and 18 presented potent effects against Mycobacterium tuberculosis (57.2 µM ≤ MIC ≤ 70.9 µM). Hydrophilic effects caused by substituents on ring B increased antibacterial activity against Gram-positive species. Thus, log P_o/w were calculated by using high-performance liquid chromatography-photodiode array detection (HPLC-PDA) analyses, and cinnamylideneacetophenones presented values ranging from 2.5 to 4.1. In addition, the effects of 3 and 4 were evaluated on pulmonary cells, indicating their moderate toxicity (46.3 µM ≤ IC₅₀ ≤ 96.7 µM) when compared with doxorubicin. Bioactive compounds were subjected to in silico prediction of pharmacokinetic properties, and did not violate Lipinski’s and Veber’s rules, corroborating their potential bioavailability by an oral route. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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1021 KiB

Open AccessArticle

Antimicrobial Effects of Violacein against Planktonic Cells and Biofilms of Staphylococcus aureus

by Andressa H. M. Batista, Anne C. D. Moreira, Rafael M. De Carvalho, Gleilton W. P. Sales, Patrícia C. N. Nogueira, Thalles B. Grangeiro, Suelen C. Medeiros, Edilberto R. Silveira and Nádia A. P. Nogueira

Molecules 2017, 22(10), 1534; https://doi.org/10.3390/molecules22101534 - 25 Sep 2017

Cited by 22 | Viewed by 5749

Abstract

Violacein is an indole compound, produced by Chromobacterium violaceum, a bacteria present in tropical and subtropical areas. Among its numerous biological activities, its antimicrobial potential stands out. This study aims to determine the antimicrobial activity of VIO on S. aureus in planktonic [...] Read more.

Violacein is an indole compound, produced by Chromobacterium violaceum, a bacteria present in tropical and subtropical areas. Among its numerous biological activities, its antimicrobial potential stands out. This study aims to determine the antimicrobial activity of VIO on S. aureus in planktonic culture and biofilms. VIO showed excellent antimicrobial activity in inhibiting and killing S. aureus in planktonic cultures and biofilm formation. The minimum bactericidal concentration (5 μg/mL) of VIO caused the death of S. aureus after 3–4 h of exposure and the minimum inhibitory concentration (1.25 μg/mL) of VIO inhibited bacterial growth within the first 8 h of contact. Biofilm formation was also strongly inhibited by VIO (1.25 μg/mL), in contrast to the higher resistance verified for S. aureus in mature biofilm (40 μg/mL). The high bacterial metabolic activity favored VIO activity; however, the good activity observed during phases of reduced metabolism indicates that VIO action involves more than one mechanism. Thus, VIO is a promising molecule for the development of an antimicrobial drug for the eradication of S. aureus infections. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Antibiofilm Activity and Mechanism of Action of the Disinfectant Chloramine T on Candida spp., and Its Toxicity against Human Cells

by Gabriela Lacet Silva Ferreira, Pedro Luiz Rosalen, Larissa Rangel Peixoto, Ana Luiza Alves de Lima Pérez, Fabíola Galbiatti de Carvalho Carlo, Lúcio Roberto Cançado Castellano, Jefferson Muniz de Lima, Irlan Almeida Freires, Edeltrudes De Oliveira Lima and Ricardo Dias de Castro

Molecules 2017, 22(9), 1527; https://doi.org/10.3390/molecules22091527 - 17 Sep 2017

Cited by 10 | Viewed by 5911

Abstract

We evaluated the antifungal and anti-biofilm activity, mechanism of action and cytotoxicity of chloramine T trihydrate (CAT) against Candida spp. The Minimum Inhibitory and Fungicidal Concentrations (MIC/MFC) of CAT were determined. Changes in CAT-treated C. albicans growth kinetics and micromorphology were evaluated, as [...] Read more.

We evaluated the antifungal and anti-biofilm activity, mechanism of action and cytotoxicity of chloramine T trihydrate (CAT) against Candida spp. The Minimum Inhibitory and Fungicidal Concentrations (MIC/MFC) of CAT were determined. Changes in CAT-treated C. albicans growth kinetics and micromorphology were evaluated, as well as the mechanism of action, and its effects on biofilm. Cytotoxicity was assessed by the hemolysis method. The data were analyzed by inferential statistics (p ≤ 0.05). CAT showed antifungal activity against all strains, with MIC values ranging between 1.38 and 5.54 mmol/L (MIC_75%: 2.77 mmol/L). CAT demonstrated an immediate and sustained action on C. albicans growth kinetics, particularly at 2 × MIC. This compound likely acts on the cell wall and membrane permeability simultaneously and was found to cause changes in C. albicans micromorphology. Tha antibiofilm activity of CAT was similar to that of sodium hypochlorite (p > 0.05) against mature biofilms. CAT was more effective than NaOCl in reducing mature biofilm upon 1-min exposure at 2 × MIC (24 h) and 4 × MIC (48 h) (p < 0.05). Toxicological analysis revealed that CAT had hemolytic activity between 61 and 67.7% as compared to 100% by NaOCl. CAT has antifungal and anti-biofilm properties, probably acting on both cell wall and membrane permeability, and showed low toxicity in vitro. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Synthesis and Antifungal Activity of Novel 3-Caren-5-One Oxime Esters

by Min Huang, Wen-Gui Duan, Gui-Shan Lin, Kun Li and Qiong Hu

Molecules 2017, 22(9), 1538; https://doi.org/10.3390/molecules22091538 - 12 Sep 2017

Cited by 14 | Viewed by 5336

Abstract

A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures [...] Read more.

A series of novel 3-caren-5-one oxime esters were designed and synthesized by multi-step reactions in an attempt to develop potent antifungal agents. Two E-Z stereoisomers of the intermediate 3-caren-5-one oxime were separated by column chromatography for the first time. The structures of all the intermediates and target compounds were confirmed by UV-Vis, FTIR, NMR, ESI-MS, and elemental analysis. The antifungal activity of the target compounds was preliminarily evaluated by the in vitro method against Fusarium oxysporum f. sp. cucumerinum, Physalospora piricola, Alternaria solani, Cercospora arachidicola, Gibberella zeae, Rhizoeotnia solani, Bipolaris maydis, and Colleterichum orbicalare at 50 µg/mL. The target compounds exhibited best antifungal activity against P. piricola, in which compounds (Z)-4r (R = β-pyridyl), (Z)-4q (R = α-thienyl), (E)-4f′ (R = p-F Ph), (Z)-4i (R = m-Me Ph), (Z)-4j (R = p-Me Ph), and (Z)-4p (R = α-furyl) had inhibition rates of 97.1%, 87.4%, 87.4%, 85.0%, 81.9%, and 77.7%, respectively, showing better antifungal activity than that of the commercial fungicide chlorothanil. Also, compound (Z)-4r (R = β-pyridyl) displayed remarkable antifungal activity against all the tested fungi, with inhibition rates of 76.7%, 82.7%, 97.1%, 66.3%, 74.7%, 93.9%, 76.7% and 93.3%, respectively, showing better or comparable antifungal activity than that of the commercial fungicide chlorothanil. Besides, the E-Z isomers of the target oxime esters were found to show obvious differences in antifungal activity. These results provide an encouraging framework that could lead to the development of potent novel antifungal agents. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Design, Synthesis, Antimycobacterial Evaluation, and In Silico Studies of 3-(Phenylcarbamoyl)-pyrazine-2-carboxylic Acids

by Lucia Semelková, Petra Janošcová, Carlos Fernandes, Ghada Bouz, Ondřej Janďourek, Klára Konečná, Pavla Paterová, Lucie Navrátilová, Jiří Kuneš, Martin Doležal and Jan Zitko

Molecules 2017, 22(9), 1491; https://doi.org/10.3390/molecules22091491 - 7 Sep 2017

Cited by 11 | Viewed by 6704

Abstract

Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, [...] Read more.

Pyrazinamide, the first-line antitubercular drug, has been regarded the basic component of tuberculosis treatment for over sixty years. Researchers have investigated its effect on Mycobacterium tuberculosis for this long time, and as a result, new potential targets of pyrazinamide or its active form, pyrazinoic acid, have been found. We have designed and prepared 3-(phenyl-carbamoyl)pyrazine-2-carboxylic acids as more lipophilic derivatives of pyrazinoic acid. We also prepared methyl and propyl derivatives as prodrugs with further increased lipophilicity. Antimycobacterial, antibacterial and antifungal growth inhibiting activity was investigated in all prepared compounds. 3-[(4-Nitrophenyl)carbamoyl]pyrazine-2-carboxylic acid (16) exerted high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 1.56 μg·mL⁻¹ (5 μM). Propyl 3-{[4-(trifluoromethyl)phenyl]carbamoyl}pyrazine-2-carboxylate (18a) showed also high antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC = 3.13 μg·mL⁻¹. In vitro cytotoxicity of the active compounds was investigated and no significant cytotoxic effect was observed. Based to structural similarity to known inhibitors of decaprenylphosphoryl-β-d-ribose oxidase, DprE1, we performed molecular docking of the prepared acids to DprE1. These in silico experiments indicate that modification of the linker connecting aromatic parts of molecule does not have any negative influence on the binding. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Synthesis and Biological Activity of Novel O-Alkyl Derivatives of Naringenin and Their Oximes

by Joanna Kozłowska, Bartłomiej Potaniec, Barbara Żarowska and Mirosław Anioł

Molecules 2017, 22(9), 1485; https://doi.org/10.3390/molecules22091485 - 6 Sep 2017

Cited by 34 | Viewed by 6556

Abstract

O-Alkyl derivatives of naringenin (1a–10a) were prepared from naringenin using the corresponding alkyl iodides and anhydrous potassium carbonate. The resulting products were used to obtain oximes (1b–10b). All compounds were tested for antimicrobial activity [...] Read more.

O-Alkyl derivatives of naringenin (1a–10a) were prepared from naringenin using the corresponding alkyl iodides and anhydrous potassium carbonate. The resulting products were used to obtain oximes (1b–10b). All compounds were tested for antimicrobial activity against Escherichia coli ATCC10536, Staphylococcus aureus DSM799, Candida albicans DSM1386, Alternaria alternata CBS1526, Fusarium linii KB-F1, and Aspergillus niger DSM1957. The resulting biological activity was expressed as the increase in optical density (ΔOD). The highest inhibitory effect against E. coli ATCC10536 was observed for 7,4′-di-O-pentylnaringenin (8a), 7-O-dodecylnaringenin (9a), naringenin oxime (NG-OX), 7,4′-di-O-pentylnaringenin oxime (8b), and 7-O-dodecylnaringenin oxime (9b) (ΔOD = 0). 7-O-dodecylnaringenin oxime (9b) also inhibited the growth of S. aureus DSM799 (ΔOD = 0.35) and C. albicans DSM1386 (ΔOD = 0.22). The growth of A. alternata CBS1526 was inhibited as a result of the action of 7,4′-di-O-methylnaringenin (2a), 7-O-ethylnaringenin (4a), 7,4′-di-O-ethylnaringenin (5a), 5,7,4′-tri-O-ethylnaringenin (6a), 7,4′-di-O-pentylnaringenin (8a), and 7-O-dodecylnaringenin (9a) (ΔOD in the range of 0.49–0.42) in comparison to that of the control culture (ΔOD = 1.87). In the case of F. linii KB-F1, naringenin (NG), 7,4′-di-O-dodecylnaringenin (10a), 7-O-dodecylnaringenin oxime (9b), and 7,4′-di-O-dodecylnaringenin oxime (10b) showed the strongest effect (ΔOD = 0). 7,4′-Di-O-pentylnaringenin (8a) and naringenin oxime (NG-OX) hindered the growth of A. niger DSM1957 (ΔOD = 0). Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Diarylethenes Display In Vitro Anti-TB Activity and Are Efficient Hits Targeting the Mycobacterium tuberculosis HU Protein

by María Angélica Suarez, Jhesua Valencia, Christian Camilo Cadena, Raktim Maiti, Chandreyee Datta, Gloria Puerto, José Hipólito Isaza, Homero San Juan, Valakunja Nagaraja and Juan David Guzman

Molecules 2017, 22(8), 1245; https://doi.org/10.3390/molecules22081245 - 25 Jul 2017

Cited by 11 | Viewed by 5489

Abstract

Tuberculosis continues to be a great source of concern in global health because of the large reservoir of humans infected with the bacilli and the appearance of clinical isolates resistant to a wide array of anti-tuberculosis drugs. New drugs with novel mechanisms of [...] Read more.

Tuberculosis continues to be a great source of concern in global health because of the large reservoir of humans infected with the bacilli and the appearance of clinical isolates resistant to a wide array of anti-tuberculosis drugs. New drugs with novel mechanisms of action on new targets are urgently required to reduce global tuberculosis burden. Mycobacterium tuberculosis nucleoid associated protein (NAP) HU has been shown to be druggable and essential for the organism’s survival. In this study, four diarylethenes were synthesized using a one-pot decarboxylated Heck-coupling of coumaric acids with iodoanisoles. The prepared compounds 1–4 were tested for their in vitro growth inhibition of M. tuberculosis H37Rv using the spot culture growth inhibition assay, displaying minimum inhibitory concentrations between 9 and 22 µM. Their cytotoxicity against BHK-21 cell line showed half inhibition at concentrations between 98 and 729 µM. The most selective hit (SI = 81), demonstrated inhibition of M. tuberculosis HU protein involved in maintaining bacterial genome architecture. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Repositioning FDA Drugs as Potential Cruzain Inhibitors from Trypanosoma cruzi: Virtual Screening, In Vitro and In Vivo Studies

by Isidro Palos, Edgar E. Lara-Ramirez, Julio Cesar Lopez-Cedillo, Carlos Garcia-Perez, Muhammad Kashif, Virgilio Bocanegra-Garcia, Benjamin Nogueda-Torres and Gildardo Rivera

Molecules 2017, 22(6), 1015; https://doi.org/10.3390/molecules22061015 - 18 Jun 2017

Cited by 37 | Viewed by 7087

Abstract

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to [...] Read more.

Chagas disease (CD) is a neglected disease caused by the parasite Trypanosoma cruzi, which affects underdeveloped countries. The current drugs of choice are nifurtimox and benznidazole, but both have severe adverse effects and less effectivity in chronic infections; therefore, the need to discover new drugs is essential. A computer-guided drug repositioning method was applied to identify potential FDA drugs (approved and withdrawn) as cruzain (Cz) inhibitors and trypanocidal effects were confirmed by in vitro and in vivo studies. 3180 FDA drugs were virtually screened using a structure-based approach. From a first molecular docking analysis, a set of 33 compounds with the best binding energies were selected. Subsequent consensus affinity binding, ligand amino acid contact clustering analysis, and ranked position were used to choose four known pharmacological compounds to be tested in vitro. Mouse blood samples infected with trypomastigotes from INC-5 and NINOA strains were used to test the trypanocidal effect of four selected compounds. Among these drugs, one fibrate antilipemic (etofyllin clofibrate) and three β-lactam antibiotics (piperacillin, cefoperazone, and flucloxacillin) showed better trypanocidal effects (LC₅₀ range 15.8–26.1 μg/mL) in comparison with benznidazole and nifurtimox (LC₅₀ range 33.1–46.7 μg/mL). A short-term in vivo evaluation of these compounds showed a reduction of parasitemia in infected mice (range 90–60%) at 6 h, but this was low compared to benznidazole (50%). This work suggests that four known FDA drugs could be used to design and obtain new trypanocidal agents. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

Design, Synthesis and Biological Evaluation of 2-(2-Amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides as Antiprotozoal Agents

by Emanuel Hernández-Núñez, Hugo Tlahuext, Rosa Moo-Puc, Diego Moreno, María Ortencia González-Díaz and Gabriel Navarrete Vázquez

Molecules 2017, 22(4), 579; https://doi.org/10.3390/molecules22040579 - 4 Apr 2017

Cited by 8 | Viewed by 5704

Abstract

Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is [...] Read more.

Parasitic diseases are a public health problem affecting millions of people worldwide. One of the scaffolds used in several drugs for the treatment of parasitic diseases is the benzimidazole moiety, a heterocyclic aromatic compound. This compound is a crucial pharmacophore group and is considered a privileged structure in medicinal chemistry. In this study, the benzimidazole core served as a model for the synthesis of a series of 2-(2-amino-5(6)-nitro-1H-benzimidazol-1-yl)-N-arylacetamides 1–8 as benznidazole analogues. The in silico pharmacological results calculated with PASS platform exhibited chemical structures highly similar to known antiprotozoal drugs. Compounds 1–8 when evaluated in silico for acute toxicity by oral dosing, were less toxic than benznidazole. The synthesis of compounds 1–8 were carried out through reaction of 5(6)-nitro-1H-benzimidazol-2-amine (12) with 2-chlroactemides 10a–h, in the presence of K₂CO₃ and acetonitrile as solvent, showing an inseparable mixture of two regioisomers with the -NO₂ group in position 5 or 6 with chemical yields of 60 to 94%. The prediction of the NMR spectra of molecule 1 coincided with the experimental chemical displacements of the regioisomers. Comparisons between the NMR prediction and the experimental data revealed that the regioisomer endo-1,6-NO₂ predominated in the reaction. The in vitro antiparasitic activity of these compounds on intestinal unicellular parasites (Giardia intestinalis and Entamoeba histolytica) and a urogenital tract parasite (Trichomonas vaginalis) were tested. Compound 7 showed an IC₅₀ of 3.95 μM and was 7 time more active against G. intestinalis than benznidazole. Compounds 7 and 8 showed 4 times more activity against T. vaginalis compared with benznidazole. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Open AccessArticle

(R)-(−)-Aloesaponol III 8-Methyl Ether from Eremurus persicus: A Novel Compound against Leishmaniosis

by Daniela Rossi, Karzan Mahmood Ahmed, Raffaella Gaggeri, Serena Della Volpe, Lauretta Maggi, Giuseppe Mazzeo, Giovanna Longhi, Sergio Abbate, Federica Corana, Emanuela Martino, Marisa Machado, Raquel Varandas, Maria Do Céu Sousa and Simona Collina

Molecules 2017, 22(4), 519; https://doi.org/10.3390/molecules22040519 - 24 Mar 2017

Cited by 23 | Viewed by 5958

Abstract

Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania [...] Read more.

Leishmaniosis is a neglected tropical disease which affects several millions of people worldwide. The current drug therapies are expensive and often lack efficacy, mainly due to the development of parasite resistance. Hence, there is an urgent need for new drugs effective against Leishmania infections. As a part of our ongoing study on the phytochemical characterization and biological investigation of plants used in the traditional medicine of western and central Asia, in the present study, we focused on Eremurus persicus root extract in order to evaluate its potential in the treatment of leishmaniosis. As a result of our study, aloesaponol III 8-methyl ether (ASME) was isolated for the first time from Eremurus persicus root extract, its chemical structure elucidated by means of IR and NMR experiments and the (R) configuration assigned by optical activity measurements: chiroptical aspects were investigated with vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectroscopies and DFT (density functional theory) quantum mechanical calculations. Concerning biological investigations, our results clearly proved that (R)-ASME inhibits Leishmania infantum promastigotes viability (IC₅₀ 73 µg/mL), inducing morphological alterations and mitochondrial potential deregulation. Moreover, it is not toxic on macrophages at the concentration tested, thus representing a promising molecule against Leishmania infections. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners

by Jelena Konstantinović, Milica Videnović, Jelena Srbljanović, Olgica Djurković-Djaković, Katarina Bogojević, Richard Sciotti and Bogdan Šolaja

Molecules 2017, 22(3), 343; https://doi.org/10.3390/molecules22030343 - 24 Feb 2017

Cited by 20 | Viewed by 6806

Abstract

Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth. Synthesized [...] Read more.

Malaria is a severe and life-threatening disease caused by Plasmodium parasites that are spread to humans through bites of infected Anopheles mosquitoes. Here, we report on the efficacy of aminoquinolines coupled to benzothiophene and thiophene rings in inhibiting Plasmodium falciparum parasite growth. Synthesized compounds were evaluated for their antimalarial activity and toxicity, in vitro and in mice. Benzothiophenes presented in this paper showed improved activities against a chloroquine susceptible (CQS) strain, with potencies of IC₅₀ = 6 nM, and cured 5/5 Plasmodium berghei infected mice when dosed orally at 160 mg/kg/day × 3 days. In the benzothiophene series, the examined antiplasmodials were more active against the CQS strain D6, than against strains chloroquine resistant (CQR) W2 and multidrug-resistant (MDR) TM91C235. For the thiophene series, a very interesting feature was revealed: hypersensitivity to the CQR strains, resistance index (RI) of <1. This is in sharp contrast to chloroquine, indicating that further development of the series would provide us with more potent antimalarials against CQR strains. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Synthesis of 16 New Hybrids from Tetrahydropyrans Derivatives and Morita˗Baylis˗Hillman Adducts: In Vitro Screening against Leishmania donovani

by Suervy Canuto de Oliveira Sousa, Juliana Da Câmara Rocha, Tatjana De Souza Lima Keesen, Everton Da Paz Silva, Priscilla Anne Castro De Assis, João Paulo Gomes De Oliveira, Saulo Luís Capim, Francisco José Seixas Xavier, Bruno Guimarães Marinho, Fábio Pedrosa Lins Silva, Claudio Gabriel Lima‐Junior and Mário Luiz Araújo de Almeida Vasconcellos

Molecules 2017, 22(2), 207; https://doi.org/10.3390/molecules22020207 - 30 Jan 2017

Cited by 10 | Viewed by 5113

Abstract

Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala‐aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The [...] Read more.

Leishmaniases are a group of neglected tropical diseases (NTDs) caused by protozoan parasites from >20 Leishmania species. Visceral leishmaniasis (VL), also known as kala‐aza, is the most severe form of leishmaniasis, usually fatal in the absence of treatment in 95% of cases. The Morita‐Baylis‐Hillman adducts (MBHAs) are being explored as drug candidates against several diseases, one of them being leishmaniasis. We present here the design, synthesis and in vitro screening against Leishmania donovani of sixteen new molecular hybrids from analgesic/antiinflammatory tetrahydropyrans derivatives and Morita˗Baylis˗Hillman adducts. First, acrylates were synthesized from analgesic/anti‐inflammatory tetrahydropyrans using acrylic acid under TsOH as a catalyst (70–75% yields). After the 16 new MBHAs were prepared in moderate to good yields (60–95%) promoted by microwave irradiation or low temperature (0 °C) in protic and aprotic medium. The hybrids were evaluated in vitro on the promastigote stage of Leishmania donovani by determining their inhibitory concentrations 50% (IC₅₀), 50% hemolysis concentration (HC₅₀), selectivity index (HC₅₀/IC₅₀,), and comparing to Amphotericin B, chosen as the anti‐leishmanial reference drug. The hybrid which presents the bromine atom in its chemical structure presents high leishmanicide activity and the high selectivity index in red blood cells (SI_rb > 180.19), compared with the highly‐toxic reference drug (SI_rb = 33.05), indicating that the bromine hybrid is a promising compound for further biological studies. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Review

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The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs

by Alicia Boto, Jose Manuel Pérez de la Lastra and Concepción C. González

Molecules 2018, 23(2), 311; https://doi.org/10.3390/molecules23020311 - 1 Feb 2018

Cited by 106 | Viewed by 10208

Abstract

Host-defense peptides, also called antimicrobial peptides (AMPs), whose protective action has been used by animals for millions of years, fulfill many requirements of the pharmaceutical industry, such as: (1) broad spectrum of activity; (2) unlike classic antibiotics, they induce very little resistance; (3) [...] Read more.

Host-defense peptides, also called antimicrobial peptides (AMPs), whose protective action has been used by animals for millions of years, fulfill many requirements of the pharmaceutical industry, such as: (1) broad spectrum of activity; (2) unlike classic antibiotics, they induce very little resistance; (3) they act synergically with conventional antibiotics; (4) they neutralize endotoxins and are active in animal models. However, it is considered that many natural peptides are not suitable for drug development due to stability and biodisponibility problems, or high production costs. This review describes the efforts to overcome these problems and develop new antimicrobial drugs from these peptides or inspired by them. The discovery process of natural AMPs is discussed, as well as the development of synthetic analogs with improved pharmacological properties. The production of these compounds at acceptable costs, using different chemical and biotechnological methods, is also commented. Once these challenges are overcome, a new generation of versatile, potent and long-lasting antimicrobial drugs is expected. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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Quinoline-Based Hybrid Compounds with Antimalarial Activity

by Xhamla Nqoro, Naki Tobeka and Blessing A. Aderibigbe

Molecules 2017, 22(12), 2268; https://doi.org/10.3390/molecules22122268 - 19 Dec 2017

Cited by 126 | Viewed by 10225

Abstract

The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by [...] Read more.

The application of quinoline-based compounds for the treatment of malaria infections is hampered by drug resistance. Drug resistance has led to the combination of quinolines with other classes of antimalarials resulting in enhanced therapeutic outcomes. However, the combination of antimalarials is limited by drug-drug interactions. In order to overcome the aforementioned factors, several researchers have reported hybrid compounds prepared by reacting quinoline-based compounds with other compounds via selected functionalities. This review will focus on the currently reported quinoline-based hybrid compounds and their preclinical studies. Full article

(This article belongs to the Special Issue Emerging Drug Discovery Approaches against Infectious Diseases)

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