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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 June 2021) | Viewed by 55886

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Prof. Dr. Marcelo J. Nieto

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Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, IL 62026-2000, USA
Interests: drug design; parallel synthesis; anti-infective drugs; natural products; antivirals
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Dear Colleagues,

Parasitic infections affect more than two billion people worldwide and account for significant morbidity and mortality throughout the world. Antiparasitic drugs are the main therapeutic treatment, but like most drugs, they have many side effects, and the risk of resistance is always a concern. Furthermore, the enormous suffering and loss of productivity translate on a large financial burden for a population that already has limited resources. Many of the parasitic diseases are considered neglected tropical diseases (NTDs) as established by the World Health Organization (WHO). Most of the current antiparasitic drugs represent no financial return on investment for the pharmaceutical industry. Indeed, the development of new or novel antiparasitic drugs have been characterized by a lack of investment from the private sector and low attention from public health.

Despite the low financial return, there is a need for novel chemical entities with a new antiparasitic mechanism of action. In this Special Issue of Pharmaceuticals, we welcome both reviews and original research articles focused on the discovery and development of new antiparasitic drugs. The proposed topics include but are not limited to:

Validation of new targets;
New chemical entities with antiparasitic activity;
Natural products;
Novel strategies for the discovery and development of antiparasitic drugs;
Mechanism of resistance.

Prof. Dr. Marcelo J. Nieto
Guest Editor

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Keywords

antiparasitic drugs
parasite resistance
small molecules
parasite
protozoa
helminth
drug discovery

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Antiparasitics 2023 in Pharmaceuticals (3 articles)

Published Papers (11 papers)

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15 pages, 2568 KiB

Open AccessArticle

Fluorescence Cross-Correlation Spectroscopy Yields True Affinity and Binding Kinetics of Plasmodium Lactate Transport Inhibitors

by Iga Jakobowska, Frank Becker, Stefano Minguzzi, Kerrin Hansen, Björn Henke, Nathan Hugo Epalle, Eric Beitz and Stefan Hannus

Pharmaceuticals 2021, 14(8), 757; https://doi.org/10.3390/ph14080757 - 2 Aug 2021

Cited by 12 | Viewed by 2761

Abstract

Blocking lactate export in the parasitic protozoan Plasmodium falciparum is a novel strategy to combat malaria. We discovered small drug-like molecules that inhibit the sole plasmodial lactate transporter, PfFNT, and kill parasites in culture. The pentafluoro-3-hydroxy-pent-2-en-1-one BH296 blocks PfFNT with nanomolar efficiency but an in vitro selected PfFNT G107S mutation confers resistance against the drug. We circumvented the mutation by introducing a nitrogen atom as a hydrogen bond acceptor site into the aromatic ring of the inhibitor yielding BH267.meta. The current PfFNT inhibitor efficiency values were derived from yeast-based lactate transport assays, yet direct affinity and binding kinetics data are missing. Here, we expressed PfFNT fused with a green fluorescent protein in human embryonic kidney cells and generated fluorescent derivatives of the inhibitors, BH296 and BH267.meta. Using confocal imaging, we confirmed the location of the proposed binding site at the cytosolic transporter entry site. We then carried out fluorescence cross-correlation spectroscopy measurements to assign true K_i-values, as well as k_on and k_off rate constants for inhibitor binding to PfFNT wildtype and the G107S mutant. BH296 and BH267.meta gave similar rate constants for binding to PfFNT wildtype. BH296 was inactive on PfFNT G107S, whereas BH267.meta bound the mutant protein albeit with weaker affinity than to PfFNT wildtype. Eventually, using a set of PfFNT inhibitor compounds, we found a robust correlation of the results from the biophysical FCCS binding assay to inhibition data of the functional transport assay. Full article

(This article belongs to the Special Issue Antiparasitics)

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15 pages, 2182 KiB

Open AccessArticle

Functional Characterization of the Oxantel-Sensitive Acetylcholine Receptor from Trichuris muris

by Tina V. A. Hansen, Richard K. Grencis, Mohamed Issouf, Cédric Neveu and Claude L. Charvet

Pharmaceuticals 2021, 14(7), 698; https://doi.org/10.3390/ph14070698 - 20 Jul 2021

Cited by 5 | Viewed by 3614

Abstract

The human whipworm, Trichuris trichiura, is estimated to infect 289.6 million people globally. Control of human trichuriasis is a particular challenge, as most anthelmintics have a limited single-dose efficacy, with the striking exception of the narrow-spectrum anthelmintic, oxantel. We recently identified a novel ACR-16-like subunit from the pig whipworm, T. suis which gave rise to a functional acetylcholine receptor (nAChR) preferentially activated by oxantel. However, there is no ion channel described in the mouse model parasite T. muris so far. Here, we have identified the ACR-16-like and ACR-19 subunits from T. muris, and performed the functional characterization of the receptors in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. We found that the ACR-16-like subunit from T. muris formed a homomeric receptor gated by acetylcholine whereas the ACR-19 failed to create a functional channel. The subsequent pharmacological analysis of the Tmu-ACR-16-like receptor revealed that acetylcholine and oxantel were equally potent. The Tmu-ACR-16-like was more responsive to the toxic agonist epibatidine, but insensitive to pyrantel, in contrast to the Tsu-ACR-16-like receptor. These findings confirm that the ACR-16-like nAChR from Trichuris spp. is a preferential drug target for oxantel, and highlights the pharmacological difference between Trichuris species. Full article

(This article belongs to the Special Issue Antiparasitics)

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15 pages, 2918 KiB

Open AccessArticle

Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni

by Raquel Porto, Ana C. Mengarda, Rayssa A. Cajas, Maria C. Salvadori, Fernanda S. Teixeira, Daniel D. R. Arcanjo, Abolghasem Siyadatpanah, Maria de Lourdes Pereira, Polrat Wilairatana and Josué de Moraes

Pharmaceuticals 2021, 14(7), 686; https://doi.org/10.3390/ph14070686 - 16 Jul 2021

Cited by 22 | Viewed by 3870

Abstract

The intravascular parasitic worm Schistosoma mansoni is a causative agent of schistosomiasis, a disease of great global public health significance. Praziquantel is the only drug available to treat schistosomiasis and there is an urgent demand for new anthelmintic agents. Adopting a phenotypic drug screening strategy, here, we evaluated the antiparasitic properties of 46 commercially available cardiovascular drugs against S. mansoni. From these screenings, we found that amiodarone, telmisartan, propafenone, methyldopa, and doxazosin affected the viability of schistosomes in vitro, with effective concentrations of 50% (EC₅₀) and 90% (EC₉₀) values ranging from 8 to 50 µM. These results were further supported by scanning electron microscopy analysis. Subsequently, the most effective drug (amiodarone) was further tested in a murine model of schistosomiasis for both early and chronic S. mansoni infections using a single oral dose of 400 mg/kg or 100 mg/kg daily for five consecutive days. Amiodarone had a low efficacy in chronic infection, with the worm and egg burden reduction ranging from 10 to 30%. In contrast, amiodarone caused a significant reduction in worm and egg burden in early infection (>50%). Comparatively, treatment with amiodarone is more effective in early infection than praziquantel, demonstrating the potential role of this cardiovascular drug as an antischistosomal agent. Full article

(This article belongs to the Special Issue Antiparasitics)

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19 pages, 8023 KiB

Open AccessArticle

Acrylonitrile Derivatives against Trypanosoma cruzi: In Vitro Activity and Programmed Cell Death Study

by Carlos J. Bethencourt-Estrella, Samuel Delgado-Hernández, Atteneri López-Arencibia, Desirée San Nicolás-Hernández, Ines Sifaoui, David Tejedor, Fernando García-Tellado, Jacob Lorenzo-Morales and José E. Piñero

Pharmaceuticals 2021, 14(6), 552; https://doi.org/10.3390/ph14060552 - 9 Jun 2021

Cited by 11 | Viewed by 3022

Abstract

The neglected infection known as Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, results in more than 7000 deaths per year, with an increasing number of cases in non-endemic areas such as Europe or the United States. Moreover, with the current available therapy, only two compounds which are active against the acute phase of the disease are readily available. In addition, these therapeutic agents display multiple undesired side effects such as high toxicity, they are expensive, the treatment is lengthy and the resistant strain has emerged. Therefore, there is a need to find new compounds against Chagas disease which should be active against the parasite but also cause low toxicity to the patients. In the present work, the activity of novel acrylonitriles against Trypanosoma cruzi was evaluated as well as the analysis of the physiological events induced in the treated parasites related to the cell death process. Hence, the characteristic features of an apoptosis-like process such as chromatin condensation and mitochondrial membrane potential, among others, were studied. From the 32 compounds tested against the epimastigote stage of T. cruzi, 11 were selected based on their selectivity index to determine if these compounds were able to induce programmed cell death (PCD) in the treated parasites. Furthermore, acrylonitriles Q5, Q7, Q19, Q27 and Q29 were shown to trigger physiological events related in the PCD. Therefore, this study highlights the therapeutic potential of acrylonitriles as novel trypanocidal agents. Full article

(This article belongs to the Special Issue Antiparasitics)

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13 pages, 1658 KiB

Open AccessArticle

Action of Carvacrol on Parascaris sp. and Antagonistic Effect on Nicotinic Acetylcholine Receptors

by Sasa M. Trailovic, Milan Rajkovic, Djordje S. Marjanovic, Cédric Neveu and Claude L. Charvet

Pharmaceuticals 2021, 14(6), 505; https://doi.org/10.3390/ph14060505 - 26 May 2021

Cited by 12 | Viewed by 3445

Abstract

Parascaris sp. is the only ascarid parasitic nematode in equids and one of the most threatening infectious organisms in horses. Only a limited number of compounds are available for treatment of horse helminthiasis, and Parascaris sp. worms have developed resistance to the three major anthelmintic families. In order to overcome the appearance of resistance, there is an urgent need for new therapeutic strategies. The active ingredients of herbal essential oils are potentially effective antiparasitic drugs. Carvacrol is one of the principal chemicals of essential oil from Origanum, Thymus, Coridothymus, Thymbra, Satureja and Lippia herbs. However, the antiparasitic mode of action of carvacrol is poorly understood. Here, the objective of the work was to characterize the activity of carvacrol on Parascaris sp. nicotinic acetylcholine receptor (nAChR) function both in vivo with the use of worm neuromuscular flap preparations and in vitro with two-electrode voltage-clamp electrophysiology on nAChRs expressed in Xenopus oocytes. We developed a neuromuscular contraction assay for Parascaris body flaps and obtained acetylcholine concentration-dependent contraction responses. Strikingly, we observed that 300 µM carvacrol fully and irreversibly abolished Parascaris sp. muscle contractions elicited by acetylcholine. Similarly, carvacrol antagonized acetylcholine-induced currents from both the nicotine-sensitive AChR and the morantel-sensitive AChR subtypes. Thus, we show for the first time that body muscle flap preparation is a tractable approach to investigating the pharmacology of Parascaris sp. neuromuscular system. Our results suggest an intriguing mode of action for carvacrol, being a potent antagonist of muscle nAChRs of Parascaris sp. worms, which may account for its antiparasitic potency. Full article

(This article belongs to the Special Issue Antiparasitics)

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14 pages, 2327 KiB

Open AccessArticle

Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds Targeting Trypanosoma cruzi Mitochondrion

by Rubén Martín-Escolano, Daniel Molina-Carreño, Daniel Plano, Socorro Espuelas, María J. Rosales, Esther Moreno, Carlos Aydillo, Carmen Sanmartín, Manuel Sánchez-Moreno and Clotilde Marín

Pharmaceuticals 2021, 14(5), 419; https://doi.org/10.3390/ph14050419 - 1 May 2021

Cited by 9 | Viewed by 2754

Abstract

Chagas disease is usually caused by tropical infection with the insect-transmitted protozoan Trypanosoma cruzi. Currently, Chagas disease is a major public health concern worldwide due to globalization, and there are no treatments neither vaccines because of the long-term nature of the disease and its complex pathology. Current treatments are limited to two obsolete drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Taking into account the urgent need for strict research efforts to find new therapies, here, we describe the in vitro and in vivo trypanocidal activity of a library of selected forty-eight selenocyanate and diselenide derivatives that exhibited leishmanicidal properties. The inclusion of selenium, an essential trace element, was due to the well-known extensive pharmacological activities for selenium compounds including parasitic diseases as T. cruzi. Here we present compound 8 as a potential compound that exhibits a better profile than benznidazole both in vitro and in vivo. It shows a fast-acting behaviour that could be attributed to its mode of action: it acts in a mitochondrion-dependent manner, causing cell death by bioenergetic collapse. This finding provides a step forward for the development of a new antichagasic agent. Full article

(This article belongs to the Special Issue Antiparasitics)

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23 pages, 2468 KiB

Open AccessArticle

New Acyl Derivatives of 3-Aminofurazanes and Their Antiplasmodial Activities

by Theresa Hermann, Patrick Hochegger, Johanna Dolensky, Werner Seebacher, Robert Saf, Marcel Kaiser, Pascal Mäser and Robert Weis

Pharmaceuticals 2021, 14(5), 412; https://doi.org/10.3390/ph14050412 - 27 Apr 2021

Cited by 3 | Viewed by 2516

Abstract

An N-acylated furazan-3-amine of a Medicines for Malaria Venture (MMV) project has shown activity against different strains of Plasmodium falciparum. Seventeen new derivatives were prepared and tested in vitro for their activities against blood stages of two strains of Plasmodium falciparum. Several structure–activity relationships were revealed. The activity strongly depended on the nature of the acyl moiety. Only benzamides showed promising activity. The substitution pattern of their phenyl ring affected the activity and the cytotoxicity of compounds. In addition, physicochemical parameters were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability) via a PAMPA. The N-(4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl)-3-(trifluoromethyl)benzamide possessed good physicochemical properties and showed high antiplasmodial activity against a chloroquine-sensitive strain (IC₅₀(NF54) = 0.019 µM) and even higher antiplasmodial activity against a multiresistant strain (IC₅₀(K₁) = 0.007 µM). Compared to the MMV compound, the permeability and the activity against the multiresistant strain were improved. Full article

(This article belongs to the Special Issue Antiparasitics)

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9 pages, 998 KiB

Open AccessFeature PaperArticle

Pipecolisporin, a Novel Cyclic Peptide with Antimalarial and Antitrypanosome Activities from a Wheat Endophytic Nigrospora oryzae

by Ignacio Fernández-Pastor, Victor González-Menéndez, Frederick Annang, Clara Toro, Thomas A. Mackenzie, Cristina Bosch-Navarrete, Olga Genilloud and Fernando Reyes

Pharmaceuticals 2021, 14(3), 268; https://doi.org/10.3390/ph14030268 - 16 Mar 2021

Cited by 14 | Viewed by 4516

Abstract

A novel cyclic antimalarial and antitrypanosome hexapeptide, pipecolisporin (1), was isolated from cultures of Nigrospora oryzae CF-298113, a fungal endophyte isolated from roots of Triticum sp. collected in a traditional agricultural land of Montefrío, Granada, Spain. The structure of this compound, including its absolute configuration, was elucidated by HRMS, 1-D and 2-D NMR spectroscopy, and Marfey’s analysis. This metabolite displayed interesting activity against Plasmodium falciparum and Trypanosoma cruzi, with IC₅₀ values in the micromolar range, and no significant cytotoxicity against the human cancer cell lines A549, A2058, MCF7, MIA PaCa-2, and HepG2. Full article

(This article belongs to the Special Issue Antiparasitics)

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17 pages, 3619 KiB

Open AccessArticle

Pharyngeal Pumping and Tissue-Specific Transgenic P-Glycoprotein Expression Influence Macrocyclic Lactone Susceptibility in Caenorhabditis elegans

by Alexander P. Gerhard, Jürgen Krücken, Cedric Neveu, Claude L. Charvet, Abdallah Harmache and Georg von Samson-Himmelstjerna

Pharmaceuticals 2021, 14(2), 153; https://doi.org/10.3390/ph14020153 - 13 Feb 2021

Cited by 13 | Viewed by 3651

Abstract

Macrocyclic lactones (MLs) are widely used drugs to treat and prevent parasitic nematode infections. In many nematode species including a major pathogen of foals, Parascaris univalens, resistance against MLs is widespread, but the underlying resistance mechanisms and ML penetration routes into nematodes remain unknown. Here, we examined how the P-glycoprotein efflux pumps, candidate genes for ML resistance, can modulate drug susceptibility and investigated the role of active drug ingestion for ML susceptibility in the model nematode Caenorhabditis elegans. Wildtype or transgenic worms, modified to overexpress P. univalens PGP-9 (Pun-PGP-9) at the intestine or epidermis, were incubated with ivermectin or moxidectin in the presence (bacteria or serotonin) or absence (no specific stimulus) of pharyngeal pumping (PP). Active drug ingestion by PP was identified as an important factor for ivermectin susceptibility, while moxidectin susceptibility was only moderately affected. Intestinal Pun-PGP-9 expression elicited a protective effect against ivermectin and moxidectin only in the presence of PP stimulation. Conversely, epidermal Pun-PGP-9 expression protected against moxidectin regardless of PP and against ivermectin only in the absence of active drug ingestion. Our results demonstrate the role of active drug ingestion by nematodes for susceptibility and provide functional evidence for the contribution of P-glycoproteins to ML resistance in a tissue-specific manner. Full article

(This article belongs to the Special Issue Antiparasitics)

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16 pages, 4120 KiB

Open AccessArticle

Antigiardial Activity of Acetylsalicylic Acid Is Associated with Overexpression of HSP70 and Membrane Transporters

by Verónica Yadira Ochoa-Maganda, Itzia Azucena Rangel-Castañeda, Daniel Osmar Suárez-Rico, Rafael Cortés-Zárate, José Manuel Hernández-Hernández, Armando Pérez-Rangel, Natalia Chiquete-Félix, Gloria León-Ávila, Sirenia González-Pozos, Jorge Gaona-Bernal and Araceli Castillo-Romero

Pharmaceuticals 2020, 13(12), 440; https://doi.org/10.3390/ph13120440 - 3 Dec 2020

Cited by 4 | Viewed by 3057

Abstract

Giardia lamblia is a flagellated protozoan responsible for giardiasis, a worldwide diarrheal disease. The adverse effects of the pharmacological treatments and the appearance of drug resistance have increased the rate of therapeutic failures. In the search for alternative therapeutics, drug repositioning has become a popular strategy. Acetylsalicylic acid (ASA) exhibits diverse biological activities through multiple mechanisms. However, the full spectrum of its activities is incompletely understood. In this study we show that ASA displayed direct antigiardial activity and affected the adhesion and growth of trophozoites in a time-dose-dependent manner. Electron microscopy images revealed remarkable morphological alterations in the membrane, ventral disk, and caudal region. Using mass spectrometry and real-time quantitative reverse transcription (qRT-PCR), we identified that ASA induced the overexpression of heat shock protein 70 (HSP70). ASA also showed a significant increase of five ATP-binding cassette (ABC) transporters (giABC, giABCP, giMDRP, giMRPL and giMDRAP1). Additionally, we found low toxicity on Caco-2 cells. Taken together, these results suggest an important role of HSPs and ABC drug transporters in contributing to stress tolerance and protecting cells from ASA-induced stress. Full article

(This article belongs to the Special Issue Antiparasitics)

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Review

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37 pages, 2598 KiB

Open AccessReview

Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects

by Gaber El-Saber Batiha, Ali Alqahtani, Omotayo B. Ilesanmi, Abdullah A. Saati, Amany El-Mleeh, Helal F. Hetta and Amany Magdy Beshbishy

Pharmaceuticals 2020, 13(8), 196; https://doi.org/10.3390/ph13080196 - 17 Aug 2020

Cited by 116 | Viewed by 20750

Abstract

Avermectins are a group of drugs that occurs naturally as a product of fermenting Streptomyces avermitilis, an actinomycetes, isolated from the soil. Eight different structures, including ivermectin, abamectin, doramectin, eprinomectin, moxidectin, and selamectin, were isolated and divided into four major components (A1a, A2a, B1a and B2a) and four minor components (A1b, A2b, B1b, and B2b). Avermectins are generally used as a pesticide for the treatment of pests and parasitic worms as a result of their anthelmintic and insecticidal properties. Additionally, they possess anticancer, anti-diabetic, antiviral, antifungal, and are used for treatment of several metabolic disorders. Avermectin generally works by preventing the transmission of electrical impulse in the muscle and nerves of invertebrates, by amplifying the glutamate effects on the invertebrates-specific gated chloride channel. Avermectin has unwanted effects or reactions, especially when administered indiscriminately, which include respiratory failure, hypotension, and coma. The current review examines the mechanism of actions, biosynthesis, safety, pharmacokinetics, biological toxicity and activities of avermectins. Full article

(This article belongs to the Special Issue Antiparasitics)

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