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Chemistry of Antiparasitic Drugs

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 27465

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Special Issue Editor

Prof. Dr. Philippe M. Loiseau

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Guest Editor

Biomolecules: Conception, Isolement, Synthese, Chatenay-Malabry, France
Interests: antiparasite chemotherapy; research of antileishmanial drugs; mechanisms of drug action; mechanisms of drug resistance; drug targeting
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I would like to announce an opportunity for you to publish an article about the chemistry of antiparasitic drugs in a Special Issue of Molecules.

New, more specific drugs and ones that are less toxic than those presently used in both medical and veterinary clinics are needed for the chemotherapy of parasitic diseases.

This objective involves different complementary approaches where chemistry is the basis of drug innovation.

Firstly, the identification of new emerging biological targets usually leads to in silico drug design approaches. Secondly, the repurposing of some drugs to the antiparasitic domain opens new possibilities of pharmacomodulations. Thirdly, in order to diminish adverse effects, it is important to modulate the drug biodistribution to concentrate the active principle where the parasites dwell in the host. Thus, chemistry has an important role in designing prodrugs for an adapted drug release and also in molecules having hydrolyzable covalent bonding with adapted drug carriers.

This Special Issue aims to provide a forum for the dissemination of the latest studies including all these approaches based on drug design, chemical synthesis, and the biological evaluation of new compounds.

I hope that you will consider submitting a manuscript for publication in this Special Issue; the deadline for manuscript submission is 31 December 2023.

Kind regards,

Prof. Dr. Philippe M. Loiseau
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

chemistry
antiparasitic drugs
drug design
chemical synthesis
in vitro and in vivo antiparasitic evaluation

Published Papers (13 papers)

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20 pages, 4611 KiB

Open AccessArticle

The Synthesis of 2′-Hydroxychalcones under Ball Mill Conditions and Their Biological Activities

by Imen Abid, Wassim Moslah, Sandrine Cojean, Nicolas Imbert, Philippe M. Loiseau, Alain Chamayou, Najet Srairi-Abid, Rachel Calvet and Michel Baltas

Molecules 2024, 29(8), 1819; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29081819 - 17 Apr 2024

Viewed by 387

Abstract

Chalcones are polyphenols that belong to the flavonoids family, known for their broad pharmacological properties. They have thus attracted the attention of chemists for their obtention and potential activities. In our study, a library of compounds from 2′-hydroxychalcone’s family was first synthesized. A one-step mechanochemical synthesis via Claisen–Schmidt condensation reaction under ball mill conditions was studied, first in a model reaction between a 5′-fluoro-2′-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde. The reaction was optimized in terms of catalysts, ratio of reagents, reaction time, and influence of additives. Among all assays, we retained the best one, which gave the highest yield of 96% when operating in the presence of 1 + 1 eq. of substituted benzaldehyde and 2 eq. of KOH under two grinding cycles of 30 min. Thus, this protocol was adopted for the synthesis of the selected library of 2′-hydroxychalcones derivatives. The biological activities of 17 compounds were then assessed against Plasmodium falciparum, Leishmania donovani parasite development, as well as IGR-39 melanoma cell lines by inhibiting their viability and proliferation. Compounds 6 and 11 are the most potent against L. donovani, exhibiting IC₅₀ values of 2.33 µM and 2.82 µM, respectively, better than the reference drug Miltefosine (3.66 µM). Compound 15 presented the most interesting antimalarial activity against the 3D7 strain, with IC₅₀ = 3.21 µM. Finally, chalcone 12 gave the best result against IGR-39 melanoma cell lines, with an IC₅₀ value of 12 µM better than the reference drug Dacarbazine (IC₅₀ = 25 µM). Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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27 pages, 7871 KiB

Open AccessArticle

Chemoselective Synthesis and Anti-Kinetoplastidal Properties of 2,6-Diaryl-4H-tetrahydro-thiopyran-4-one S-Oxides: Their Interplay in a Cascade of Redox Reactions from Diarylideneacetones

by Thibault Gendron, Don Antoine Lanfranchi, Nicole I. Wenzel, Hripsimée Kessedjian, Beate Jannack, Louis Maes, Sandrine Cojean, Thomas J. J. Müller, Philippe M. Loiseau and Elisabeth Davioud-Charvet

Molecules 2024, 29(7), 1620; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29071620 - 04 Apr 2024

Viewed by 413

Abstract

2,6-Diaryl-4H-tetrahydro-thiopyran-4-ones and corresponding sulfoxide and sulfone derivatives were designed to lower the major toxicity of their parent anti-kinetoplatidal diarylideneacetones through a prodrug effect. Novel diastereoselective methodologies were developed and generalized from diarylideneacetones and 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones to allow the introduction of a wide substitution profile and to prepare the related S-oxides. The in vitro biological activity and selectivity of diarylideneacetones, 2,6-diaryl-4H-tetrahydro-thiopyran-4-ones, and their S-sulfoxide and sulfone metabolites were evaluated against Trypanosoma brucei brucei, Trypanosoma cruzi, and various Leishmania species in comparison with their cytotoxicity against human fibroblasts hMRC-5. The data revealed that the sulfides, sulfoxides, and sulfones, in which the Michael acceptor sites are temporarily masked, are less toxic against mammal cells while the anti-trypanosomal potency was maintained against T. b. brucei, T. cruzi, L. infantum, and L. donovani, thus confirming the validity of the prodrug strategy. The mechanism of action is proposed to be due to the involvement of diarylideneacetones in cascades of redox reactions involving the trypanothione system. After Michael addition of the dithiol to the double bonds, resulting in an elongated polymer, the latter—upon S-oxidation, followed by syn-eliminations—fragments, under continuous release of reactive oxygen species and sulfenic/sulfonic species, causing the death of the trypanosomal parasites in the micromolar or submicromolar range with high selectivity indexes. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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19 pages, 6753 KiB

Open AccessArticle

Hybrid Peptide-Alkoxyamine Drugs: A Strategy for the Development of a New Family of Antiplasmodial Drugs

by Ange W. Embo-Ibouanga, Michel Nguyen, Lucie Paloque, Mathilde Coustets, Jean-Patrick Joly, Jean-Michel Augereau, Nicolas Vanthuyne, Raphaël Bikanga, Naomie Coquin, Anne Robert, Gérard Audran, Jérôme Boissier, Philippe Mellet, Françoise Benoit-Vical and Sylvain R. A. Marque

Molecules 2024, 29(6), 1397; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29061397 - 21 Mar 2024

Viewed by 695

Abstract

The emergence and spread of drug-resistant Plasmodium falciparum parasites shed a serious concern on the worldwide control of malaria, the most important tropical disease in terms of mortality and morbidity. This situation has led us to consider the use of peptide-alkoxyamine derivatives as new antiplasmodial prodrugs that could potentially be efficient in the fight against resistant malaria parasites. Indeed, the peptide tag of the prodrug has been designed to be hydrolysed by parasite digestive proteases to afford highly labile alkoxyamines drugs, which spontaneously and instantaneously homolyse into two free radicals, one of which is expected to be active against P. falciparum. Since the parasite enzymes should trigger the production of the active drug in the parasite’s food vacuoles, our approach is summarized as “to dig its grave with its fork”. However, despite promising sub-micromolar IC₅₀ values in the classical chemosensitivity assay, more in-depth tests evidenced that the anti-parasite activity of these compounds could be due to their cytostatic activity rather than a truly anti-parasitic profile, demonstrating that the antiplasmodial activity cannot be based only on measuring antiproliferative activity. It is therefore imperative to distinguish, with appropriate tests, a genuinely parasiticidal activity from a cytostatic activity. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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14 pages, 1912 KiB

Open AccessCommunication

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline

by Gwenaëlle Jézéquel, Laura Nogueira de Faria Cardoso, Florent Olivon, Indira Dennemont, Cécile Apel, Marc Litaudon, Fanny Roussi, Sébastien Pomel and Sandy Desrat

Molecules 2022, 27(22), 7892; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227892 - 15 Nov 2022

Cited by 2 | Viewed by 1300

Abstract

Quinoline derivatives and especially quinolones are considered as privileged structures in medicinal chemistry and are often associated with various biological properties. We recently isolated a series of original monoterpenyl quinolones from the bark of Codiaeum peltatum. As this extract was found to have a significant inhibitory activity against a Leishmania species, we decided to study the anti-leishmanial potential of this type of compound. Leishmaniasis is a serious health problem affecting more than 12 million people in the world. Available drugs cause harmful side effects and resistance for some of them. With the aim of finding anti-leishmanial compounds, we developed a synthetic strategy to access natural quinolones and analogues derived from zanthosimuline. We showed the versatility of this natural compound toward cyclization conditions, leading to various polycyclic quinolone-derived structures. The natural and synthetic compounds were evaluated against amastigote forms of Leishmania infantum. The results obtained confirmed the interest of this family of natural compounds but also revealed promising activities for some intermediates deriving from zanthosimuline. Following the same synthetic strategy, we then prepared 14 new analogues. In this work, we identified two promising molecules with good activities against intramacrophage L. infantum amastigotes without any cytotoxicity. We also showed that slight changes in amide functional groups affect drastically their anti-parasitic activity. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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22 pages, 4162 KiB

Open AccessFeature PaperArticle

Antileishmanial Anthracene Endoperoxides: Efficacy In Vitro, Mechanisms and Structure-Activity Relationships

by Laura Machin, Martin Piontek, Sara Todhe, Katrin Staniek, Lianet Monzote, Werner Fudickar, Torsten Linker and Lars Gille

Molecules 2022, 27(20), 6846; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27206846 - 13 Oct 2022

Viewed by 1387

Abstract

Leishmaniasis is a vector-borne disease caused by protozoal Leishmania parasites. Previous studies have shown that endoperoxides (EP) can selectively kill Leishmania in host cells. Therefore, we studied in this work a set of new anthracene-derived EP (AcEP) together with their non-endoperoxidic analogs in model systems of Leishmania tarentolae promastigotes (LtP) and J774 macrophages for their antileishmanial activity and selectivity. The mechanism of effective compounds was explored by studying their reaction with iron (II) in chemical systems and in Leishmania. The correlation of structural parameters with activity demonstrated that in this compound set, active compounds had a LogP_OW larger than 3.5 and a polar surface area smaller than 100 Å². The most effective compounds (IC₅₀ in LtP < 2 µM) with the highest selectivity (SI > 30) were pyridyl-/tert-butyl-substituted AcEP. Interestingly, also their analogs demonstrated activity and selectivity. In mechanistic studies, it was shown that EP were activated by iron in chemical systems and in LtP due to their EP group. However, the molecular structure beyond the EP group significantly contributed to their differential mitochondrial inhibition in Leishmania. The identified compound pairs are a good starting point for subsequent experiments in pathogenic Leishmania in vitro and in animal models. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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14 pages, 4080 KiB

Open AccessArticle

Evaluation of Anthelmintic and Anti-Inflammatory Activity of 1,2,4-Triazole Derivatives

by Renata Paprocka, Przemysław Kołodziej, Małgorzata Wiese-Szadkowska, Anna Helmin-Basa and Anna Bogucka-Kocka

Molecules 2022, 27(14), 4488; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144488 - 13 Jul 2022

Cited by 13 | Viewed by 1721

Abstract

Parasitic diseases, caused by intestinal helminths, remain a very serious problem in both human and veterinary medicine. While searching for new nematicides we examined a series of 1,2,4-triazole derivatives 9–22, obtained during reactions of N³-substituted amidrazones with itaconic anhydride. Two groups of compounds, 9–16 and 17–22, differed in the position of the double bond on the methacrylic acid moiety. The toxicity of derivatives 9–22 and the anti-inflammatory activity of 12 and 19–22 were studied on peripheral blood mononuclear cells (PBMC). Antiproliferative activity of compounds 12 and 19–22 was tested cytometrically in PBMC cultures stimulated by phytohemagglutinin. The influence of derivatives 12 and 19–22 on the TNF-α, IL-6, IL-10 and IFN-γ production was determined by ELISA in lipopolysaccharide-stimulated PBMC cultures. Anthelmintic activity of compounds 10–22 was studied in the Rhabditis sp. nematodes model. Most compounds (11–22) proved to be non-toxic to human PBMC. Derivatives 19–22 showed anti-inflammatory activity by inhibiting the proliferation of lymphocytes. Moreover, compounds 12 and 19–22 significantly reduced the production of TNF-α and derivatives 19–21 decreased the level of INF-γ. The strongest anti-inflammatory activity was observed for compound 21. Compounds 12 and 14 demonstrated anthelmintic activity higher than albendazole and may become promising candidates for anthelmintic drugs. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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19 pages, 10129 KiB

Open AccessArticle

Structure-Based Bioisosterism Design, Synthesis, Biological Evaluation and In Silico Studies of Benzamide Analogs as Potential Anthelmintics

by Franco Vairoletti, Margot Paulino, Graciela Mahler, Gustavo Salinas and Cecilia Saiz

Molecules 2022, 27(9), 2659; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092659 - 20 Apr 2022

Cited by 1 | Viewed by 2529

Abstract

A recent screen of 67,012 compounds identified a new family of compounds with excellent nematicidal activity: the ortho-substituted benzamide families Wact-11 and Wact-12. These compounds are active against Caenorhabditis elegans and parasitic nematodes by selectively inhibiting nematode complex II, and they display low toxicity in mammalian cells and vertebrate organisms. Although a big number of benzamides were tested against C. elegans in high-throughput screens, bioisosteres of the amide moiety were not represented in the chemical space examined. We thus identified an opportunity for the design, synthesis and evaluation of novel compounds, using bioisosteric replacements of the amide group present in benzamides. The compound Wact-11 was used as the reference scaffold to prepare a set of bioisosteres to be evaluated against C. elegans. Eight types of amide replacement were selected, including ester, thioamide, selenoamide, sulfonamide, alkyl thio- and oxo-amides, urea and triazole. The results allowed us to perform a structure–activity relationship, highlighting the relevance of the amide group for nematicide activity. Experimental evidence was complemented with in silico structural studies over a C. elegans complex II model as a molecular target of benzamides. Importantly, compound Wact-11 was active against the flatworm Echinococcus granulosus, suggesting a previously unreported pan-anthelmintic potential for benzamides. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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18 pages, 3757 KiB

Open AccessArticle

Discovery of Cinnamylidene Derivative of Rhodanine with High Anthelmintic Activity against Rhabditis sp.

by Waldemar Tejchman, Przemysław Kołodziej, Justyna Kalinowska-Tłuścik, Wojciech Nitek, Grzegorz Żuchowski, Anna Bogucka-Kocka and Ewa Żesławska

Molecules 2022, 27(7), 2155; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072155 - 27 Mar 2022

Cited by 6 | Viewed by 2733

Abstract

The treatment of parasitic infections requires the application of chemotherapy. In view of increasing resistance to currently in-use drugs, there is a constant need to search for new compounds with anthelmintic activity. A series of 16 cinnamylidene derivatives of rhodanine, including newly synthesized methoxy derivatives (1–11) and previously obtained chloro, nitro, and diethylamine derivatives (12–16), was investigated towards anthelmintic activity. Compounds (1–16) were evaluated against free-living nematodes of the genus Rhabditis sp. In the tested group of rhodanine derivatives, only compound 2 shows very high biological activity (LC₅₀ = 0.93 µg/µL), which is higher than the reference drug albendazole (LC₅₀ = 19.24 µg/µL). Crystal structures of two compounds, active 2 and inactive 4, were determined by the X-ray diffraction method to compare molecular geometry and search for differences responsible for observed biological activity/inactivity. Molecular modelling and selected physicochemical properties prediction were performed to assess the potential mechanism of action and applied in the search for an explanation as to why amongst all similar compounds only one is active. We can conclude that the tested compound 2 can be further investigated as a potential anthelmintic drug. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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10 pages, 874 KiB

Open AccessArticle

Absorption and Distribution of Toltrazuril and Toltrazuril Sulfone in Plasma, Intestinal Tissues and Content of Piglets after Oral or Intramuscular Administration

by Hamadi Karembe, Daniel Sperling, Nathalie Varinot, Reynald Magnier, Mathieu Peyrou, Nicolas Guerra, Jiří Smola, Jan Vasek, Barbara Hinney and Anja Joachim

Molecules 2021, 26(18), 5633; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185633 - 16 Sep 2021

Cited by 6 | Viewed by 2647

Abstract

Piglet coccidiosis due to Cystoisospora suis is a major cause of diarrhea and poor growth worldwide. It can effectively be controlled by application of toltrazuril (TZ), and oral formulations have been licensed for many years. Recently, the first parenteral formulation containing TZ in combination with iron (gleptoferron) was registered in the EU for the prevention of coccidiosis and iron deficiency anemia, conditions in suckling piglets requiring routine preventive measures. This study evaluated the absorption and distribution of TZ and its main metabolite, toltrazuril sulfone (TZ-SO₂), in blood and intestinal tissues after single oral (20 mg/kg) or single intramuscular (45 mg/piglet) application of TZ. Fifty-six piglets were randomly allocated to the two treatment groups. Animals were sacrificed 1-, 5-, 13-, and 24-days post-treatment and TZ and TZ-SO₂ levels were determined in blood, jejunal tissue, ileal tissue, and mixed jejunal and ileal content (IC) by high performance liquid chromatography (HPLC). Intramuscular application resulted in significantly higher and more sustained concentrations of both compounds in plasma, intestinal tissue, and IC. Higher concentrations after oral dosing were only observed one day after application of TZ in jejunum and IC. Toltrazuril was quickly metabolized to TZ-SO₂ with maximum concentrations on day 13 for both applications. Remarkably, TZ and TZ-SO₂ accumulated in the jejunum, the primary predilection site of C. suis, independently of the administration route, which is key to their antiparasitic effect. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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Review

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18 pages, 343 KiB

Open AccessReview

Drug Repurposing in the Chemotherapy of Infectious Diseases

by Amal Hamid, Pascal Mäser and Abdelhalim Babiker Mahmoud

Molecules 2024, 29(3), 635; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules29030635 - 29 Jan 2024

Viewed by 863

Abstract

Repurposing is a universal mechanism for innovation, from the evolution of feathers to the invention of Velcro tape. Repurposing is particularly attractive for drug development, given that it costs more than a billion dollars and takes longer than ten years to make a new drug from scratch. The COVID-19 pandemic has triggered a large number of drug repurposing activities. At the same time, it has highlighted potential pitfalls, in particular when concessions are made to the target product profile. Here, we discuss the pros and cons of drug repurposing for infectious diseases and analyze different ways of repurposing. We distinguish between opportunistic and rational approaches, i.e., just saving time and money by screening compounds that are already approved versus repurposing based on a particular target that is common to different pathogens. The latter can be further distinguished into divergent and convergent: points of attack that are divergent share common ancestry (e.g., prokaryotic targets in the apicoplast of malaria parasites), whereas those that are convergent arise from a shared lifestyle (e.g., the susceptibility of bacteria, parasites, and tumor cells to antifolates due to their high rate of DNA synthesis). We illustrate how such different scenarios can be capitalized on by using examples of drugs that have been repurposed to, from, or within the field of anti-infective chemotherapy. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

21 pages, 2740 KiB

Open AccessReview

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

by Philippe M. Loiseau, Kaluvu Balaraman, Gillian Barratt, Sébastien Pomel, Rémy Durand, Frédéric Frézard and Bruno Figadère

Molecules 2022, 27(7), 2313; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27072313 - 02 Apr 2022

Cited by 9 | Viewed by 2161

Abstract

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC₅₀ value of 0.2 µM against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure–activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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24 pages, 12301 KiB

Open AccessReview

The Current Directions of Searching for Antiparasitic Drugs

by Katarzyna Dziduch, Dominika Greniuk and Monika Wujec

Molecules 2022, 27(5), 1534; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27051534 - 24 Feb 2022

Cited by 10 | Viewed by 3972

Abstract

Parasitic diseases are still a huge problem for mankind. They are becoming the main cause of chronic diseases in the world. Migration of the population, pollution of the natural environment, and climate changes cause the rapid spread of diseases. Additionally, a growing resistance of parasites to drugs is observed. Many research groups are looking for effective antiparasitic drugs with low side effects. In this work, we present the current trends in the search for antiparasitic drugs. We report known drugs used in other disease entities with proven antiparasitic activity and research on new chemical structures that may be potential drugs in parasitic diseases. The described investigations of antiparasitic compounds can be helpful for further drug development. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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34 pages, 15858 KiB

Open AccessReview

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine

by Dawid J. Kucharski, Michalina K. Jaszczak and Przemysław J. Boratyński

Molecules 2022, 27(3), 1003; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27031003 - 02 Feb 2022

Cited by 22 | Viewed by 4915

Abstract

Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments. Full article

(This article belongs to the Special Issue Chemistry of Antiparasitic Drugs)

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