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Pharmaceuticals
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Drug Discovery and Evaluation for the Treatment of Parasitic Infections
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Drug Discovery and Evaluation for the Treatment of Parasitic Infections

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 25664

Special Issue Editors

Dr. Gabriela Hrckova

E-Mail Website
Guest Editor
Institute of Parasitology, Slovak Academy of Sciences, Hlinkova 3, 04001 Košice, Slovakia
Interests: Biotechnology; Infection; Natural Product Chemistry; Biomedical Science; Immunology; Treatment; Cell Biology; Antibodies; Immunity; Cancer Research;
Prof. Dr. Gustavo Henrique Goulart Trossini

E-Mail Website
Guest Editor
Departamento de Farmácia, Universidade de São Paulo, Sao Paulo, Brazil
Interests: medicinal chemistry; molecular modelling of drug-target interactions; virtual drug screening; parasitic diseases

Special Issue Information

Dear Colleagues,

Infectious diseases caused by parasitic protozoan and metazoan species, in spite of an immense effort put into eradication programmes within the past decades, are still on the list of the most frequently encountered diseases, mostly in tropical countries. Nowadays, the therapy and prevention of parasitic infections are facing several major issues: the emergence and rapid spread of resistant strains of parasites and the limited number of safe and highly effective antiparasitic drugs. Parasites have a fascinating biology and developed interesting strategies for survival in the hosts. Ongoing research revealed unique biochemical and molecular targets to be explored in drug discovery by the rational approach. Drug discovery is a multidisciplinary approach that span the chemistry and biology disciplines.

The potential topics of this thematic issue can cover research papers or reviews dealing with:

  • Screening of antiparasitic activity of secondary metabolites and other specific molecules from higher plants and low organisms (fungi, lichens, marine plants, and others) on in vitro parasitic models. Rational approach to drug discovery focussing on molecules interfering with specific molecular targets in parasites (for example, inhibitors of receptors, signalling pathways, proteins of the mitochondrial respiratory chain, antioxidants or other types of enzymes, parasitic microRNAs, etc.).
  • Compounds developed by a medicinal chemistry approach, structure-based drug discovery targeting pathogens, chemically modified molecules using natural motifs, innovative drug formulations, repurposing of drugs.
  • Validation of the in vitro-detected antiparasitic activities of selected compounds on the experimental diseases using mouse or other models. Evaluation of the immunomodulatory effects towards the elevation of drug efficacy.
  • Combination therapy as a means to maintain in vivo the synergistic ratio of the drugs combination by co-incorporation of both immunomodulatory and chemotherapeutic agents.

Dr. Gabriela Hrckova
Prof. Dr. Gustavo Henrique Goulart Trossini
Guest Editors

Manuscript Submission Information

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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. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • parasitic diseases of humans and animals
  • protozoan and metazoan parasites
  • drug discovery
  • rational approach
  • natural products, synthetic derivates
  • combined therapy and immunomodulation
  • repurposing of drugs

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Published Papers (9 papers)

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Research

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14 pages, 1662 KiB  
Article
Trypanosoma cruzi Sirtuin 2 as a Relevant Druggable Target: New Inhibitors Developed by Computer-Aided Drug Design
by Glaucio Monteiro Ferreira, Thales Kronenberger, Vinicius Gonçalves Maltarollo, Antti Poso, Fernando de Moura Gatti, Vitor Medeiros Almeida, Sandro Roberto Marana, Carla Duque Lopes, Daiane Yukie Tezuka, Sérgio de Albuquerque, Flavio da Silva Emery and Gustavo Henrique Goulart Trossini
Pharmaceuticals 2023, 16(3), 428; https://doi.org/10.3390/ph16030428 - 10 Mar 2023
Cited by 2 | Viewed by 2630
Abstract
Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD+-dependent class III histone deacetylase, to interfere with the parasites’ [...] Read more.
Trypanosoma cruzi, the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD+-dependent class III histone deacetylase, to interfere with the parasites’ cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC50 = 40 μM) was chosen as a potential lead compound. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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16 pages, 1251 KiB  
Article
The Parasite Reduction Ratio (PRR) Assay Version 2: Standardized Assessment of Plasmodium falciparum Viability after Antimalarial Treatment In Vitro
by Annabelle Walz, Maëlle Duffey, Ghaith Aljayyoussi, Sibylle Sax, Didier Leroy, Dominique Besson, Jeremy N. Burrows, Mohammed H. Cherkaoui-Rbati, Nathalie Gobeau, Marie-Anne Westwood, Christoph Siethoff, Francisco-Javier Gamo, Pascal Mäser and Sergio Wittlin
Pharmaceuticals 2023, 16(2), 163; https://doi.org/10.3390/ph16020163 - 23 Jan 2023
Cited by 9 | Viewed by 3412
Abstract
With artemisinin-resistant Plasmodium falciparum parasites emerging in Africa, the need for new antimalarial chemotypes is persistently high. The ideal pharmacodynamic parameters of a candidate drug are a rapid onset of action and a fast rate of parasite killing or clearance. To determine these [...] Read more.
With artemisinin-resistant Plasmodium falciparum parasites emerging in Africa, the need for new antimalarial chemotypes is persistently high. The ideal pharmacodynamic parameters of a candidate drug are a rapid onset of action and a fast rate of parasite killing or clearance. To determine these parameters, it is essential to discriminate viable from nonviable parasites, which is complicated by the fact that viable parasites can be metabolically inactive, whilst dying parasites can still be metabolically active and morphologically unaffected. Standard growth inhibition assays, read out via microscopy or [3H] hypoxanthine incorporation, cannot reliably discriminate between viable and nonviable parasites. Conversely, the in vitro parasite reduction ratio (PRR) assay is able to measure viable parasites with high sensitivity. It provides valuable pharmacodynamic parameters, such as PRR, 99.9% parasite clearance time (PCT99.9%) and lag phase. Here we report the development of the PRR assay version 2 (V2), which comes with a shorter assay duration, optimized quality controls and an objective, automated analysis pipeline that systematically estimates PRR, PCT99.9% and lag time and returns meaningful secondary parameters such as the maximal killing rate of a drug (Emax) at the assayed concentration. These parameters can be fed directly into pharmacokinetic/pharmacodynamic models, hence aiding and standardizing lead selection, optimization, and dose prediction. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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23 pages, 3503 KiB  
Article
Preclinical Studies and Drug Combination of Low-Cost Molecules for Chagas Disease
by Elena Aguilera, Carina Sánchez, María Eugenia Cruces, Belén Dávila, Lucía Minini, Florencia Mosquillo, Leticia Pérez-Díaz, Elva Serna, Susana Torres, Alicia Schini, Luis Sanabria, Ninfa I. Vera de Bilbao, Gloria Yaluff, Flavio R. Zolessi, Luis Fabian Ceilas, Hugo Cerecetto and Guzmán Alvarez
Pharmaceuticals 2023, 16(1), 20; https://doi.org/10.3390/ph16010020 - 23 Dec 2022
Cited by 1 | Viewed by 2291
Abstract
Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different [...] Read more.
Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics). Previously, we described a series of compounds with simple structures, low cost, and environmentally friendly production with potent trypanosomicidal activity in vitro and in vivo. These molecules are from three different families: thiazolidenehydrazines, diarylideneketones, and steroids. From this collection, we explored their capacity to inhibit the triosephosphate isomerase and cruzipain of T. cruzi. Then, the mechanism of action was explored using NMR metabolomics and computational molecular dynamics. Moreover, the mechanism of death was studied by flow cytometry. Consequently, five compounds, 314, 793, 1018, 1019, and 1260, were pre-clinically studied and their pharmacologic profiles indicated low unspecific toxicity. Interestingly, synergetic effects of diarylideneketones 793 plus 1018 and 793 plus 1019 were evidenced in vitro and in vivo. In vivo, the combination of compounds 793 plus 1018 induced a reduction of more than 90% of the peak of parasitemia in the acute murine model of Chagas disease. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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19 pages, 1333 KiB  
Article
Human Lung Cancer (A549) Cell Line Cytotoxicity and Anti-Leishmania major Activity of Carissa macrocarpa Leaves: A Study Supported by UPLC-ESI-MS/MS Metabolites Profiling and Molecular Docking
by Mohamed A. A. Orabi, Omaish Salman Alqahtani, Bandar A. Alyami, Ahmed Abdullah Al Awadh, El-Shaymaa Abdel-Sattar, Katsuyoshi Matsunami, Dalia I. Hamdan and Mohamed E. Abouelela
Pharmaceuticals 2022, 15(12), 1561; https://doi.org/10.3390/ph15121561 - 14 Dec 2022
Cited by 3 | Viewed by 2452
Abstract
Lung cancer and cutaneous leishmaniasis are critical diseases with a relatively higher incidence in developing countries. In this research, the activity of Carissa macrocarpa leaf hydromethanolic extract and its solvent-fractions (n-hexane, EtOAc, n-butanol, and MeOH) against the lung adenocarcinoma cell [...] Read more.
Lung cancer and cutaneous leishmaniasis are critical diseases with a relatively higher incidence in developing countries. In this research, the activity of Carissa macrocarpa leaf hydromethanolic extract and its solvent-fractions (n-hexane, EtOAc, n-butanol, and MeOH) against the lung adenocarcinoma cell line (A549) and Leishmania major was investigated. The MeOH fraction exhibited higher cytotoxic activity (IC50 1.57 ± 0.04 μg/mL) than the standard drug, etoposide (IC50 50.8 ± 3.16 μg/mL). The anti-L. major results revealed strong growth inhibitory effects of the EtOAc fraction against L. major promastigotes (IC50 27.52 ± 0.7 μg/mL) and axenic amastigotes (29.33 ± 4.86% growth inhibition at 100 μg/mL), while the butanol fraction exerted moderate activity against promastigotes (IC50 73.17 ± 1.62), as compared with miltefosine against promastigotes (IC50 6.39 ± 0.29 μg/mL) and sodium stibogluconate against axenic amastigotes (IC50 22.45 ± 2.22 μg/mL). A total of 102 compounds were tentatively identified using UPLC-ESI-MS/MS analysis of the total extract and its fractions. The MeOH fraction was found to contain several flavonoids and flavan-3-ol derivatives with known cytotoxic properties, whereas the EtOAc fractions contained triterpene, hydroxycinnamoyl, sterol, and flavanol derivatives with known antileishmanial activity. Molecular docking of various polyphenolics of the MeOH fraction with HDAC6 and PDK3 enzymes demonstrates high binding affinity of the epicatechin 3-O-β-D-glucopyranoside and catechin-7-O-β-D-glucopyranoside toward HDAC6, and procyanidin C2, procyanidin B5 toward PDK3. These results are promising and encourage the pursuit of preclinical research using C. macrocarpa’s MeOH fraction as anti-lung cancer and the EtOAc fraction as an anti-L. major drug candidates. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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23 pages, 1225 KiB  
Article
New Derivatives of the Multi-Stage Active Malaria Box Compound MMV030666 and Their Antiplasmodial Potencies
by Theresa Hermann, Robin Wallner, Johanna Dolensky, Werner Seebacher, Eva-Maria Pferschy-Wenzig, Marcel Kaiser, Pascal Mäser and Robert Weis
Pharmaceuticals 2022, 15(12), 1503; https://doi.org/10.3390/ph15121503 - 2 Dec 2022
Viewed by 1600
Abstract
MMV’s Malaria Box compound MMV030666 shows multi-stage activity against various strains of Plasmodium falciparum and lacks resistance development. To evaluate the importance of its diarylether partial structure, diarylthioethers and diphenylamines with varying substitution patterns were prepared. A number of evident structure-activity relationships were [...] Read more.
MMV’s Malaria Box compound MMV030666 shows multi-stage activity against various strains of Plasmodium falciparum and lacks resistance development. To evaluate the importance of its diarylether partial structure, diarylthioethers and diphenylamines with varying substitution patterns were prepared. A number of evident structure-activity relationships were revealed. Physicochemical and pharmacokinetic parameters were determined experimentally (passive permeability) or calculated. Compared to the lead compound a diarylthioether was more active and less cytotoxic resulting in an excellent selectivity index of 850. In addition, pharmacokinetic and physicochemical parameters were improved. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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15 pages, 2881 KiB  
Article
Adherent Bacteria and Parasiticidal Secretion Products of Human Cervicovaginal Microbiota-Associated Lactobacillus gasseri Confer Non-Identical Cell Protection against Trichomonas vaginalis-Induced Cell Detachment
by Bénédicte Pradines, Séverine Domenichini and Vanessa Lievin-Le Moal
Pharmaceuticals 2022, 15(11), 1350; https://doi.org/10.3390/ph15111350 - 31 Oct 2022
Cited by 5 | Viewed by 2380
Abstract
Trichomonas vaginalis, a protozoan parasite specific to the human genital tract, is one of the most common sexually transmitted pathogens. Its pathogenicity is strongly associated with its expression of a broad array of proteases triggering cytotoxic effects in host epithelial cells. Vaginal [...] Read more.
Trichomonas vaginalis, a protozoan parasite specific to the human genital tract, is one of the most common sexually transmitted pathogens. Its pathogenicity is strongly associated with its expression of a broad array of proteases triggering cytotoxic effects in host epithelial cells. Vaginal microbiota-associated Lactobacillus, including those of L. gasseri in particular, can counteract T. vaginalis pathogenesis, but the mechanisms involved have yet to be clarified. T. vaginalis strain G3 (Tv G3) cytotoxicity was assessed by examining cell morphology, cell detachment, and fluorescent labeling of the F-actin cytoskeleton and immunolabeling of vinculin-position focal adhesions (FAs) by confocal laser scanning electron microscopy on confluent cervicovaginal epithelial HeLa cell monolayers. The inhibitory effects of bacterial cells and secreted products of L. gasseri ATCC 9857 and KS 120.1 on the Tv G3 viability and parasite deleterious effects on HeLa cells were investigated. Pre-adhering L. gasseri cells delayed but did not inhibit Tv G3-induced cell detachment, F-actin cytoskeleton disorganization and the disappearance of vinculin-positive focal FAs. L. gasseri KS 120.1 secretion products had a rapid parasiticide activity by killing time- and concentration-dependent Tv G3 parasites after direct contact. By killing Tv G3 parasites already associated with the epithelial cells, secretion products have abolished parasite-induced cell detachment. Our findings suggest that vagina microbiota-associated L. gasseri creates a physical barrier and exerts pharmacological-type mechanisms to counteract the deleterious cytotoxic effects of T. vaginalis. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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15 pages, 3642 KiB  
Article
Copper (I)-Chloroquine Complexes: Interactions with DNA and Ferriprotoporphyrin, Inhibition of β-Hematin Formation and Relation to Antimalarial Activity
by Wilmer Villarreal, William Castro, Sorenlis González, Marylin Madamet, Rémy Amalvict, Bruno Pradines and Maribel Navarro
Pharmaceuticals 2022, 15(8), 921; https://doi.org/10.3390/ph15080921 - 25 Jul 2022
Cited by 9 | Viewed by 1990
Abstract
A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be [...] Read more.
A new Cu(I)-chloroquine (CQ) complex [Cu(CQ)(PPh3)2]NO3 (1) was synthesized and characterized, and its mechanism of action studied concomitant with the previously reported complex [Cu(CQ)2]Cl (2). These copper (I) coordination compounds can be considered as potential antimalarial agents because they show better inhibition of the CQ-resistant strain in in vitro studies than CQ alone. In comparison with other metal-CQ complexes, only the gold complex was similar to (1), i.e., more active than CQ against both CQ-susceptible (3D7) and CQ-resistant strains (W2). These two copper (I)-compounds also demonstrated higher antiplasmodial activity against W2 than other copper complexes reported to date. This suggests that the incorporation of the copper metal center enhanced the biological activity of CQ. To better understand their significant growth inhibition of the Plasmodium falciparum parasite, the interaction with two essential molecular targets for the survival and proliferation of the malarial parasite were studied. These were the ferriprotoporphyrin group and the DNA, both important targets for current antimalarial drugs at the asexual erythrocytic stages. Both compounds (1,2) exhibited significant interactions with these targets. In particular, interactions with the DNA were dominated by the intercalator properties of the CQ ligand but may have also been affected by the presence of copper. Overall, these compounds were better parasitic inhibitors than chloroquine diphosphate (CQDP) alone or other previously reported metal-CQ complexes such as platinum, ruthenium and gold. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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19 pages, 2510 KiB  
Article
Therapeutic Efficacy of Arnica in Hamsters with Cutaneous Leishmaniasis Caused by Leishmania braziliensis and L. tropica
by Sara M. Robledo, Javier Murillo, Natalia Arbeláez, Andrés Montoya, Victoria Ospina, Franziska M. Jürgens, Iván D. Vélez and Thomas J. Schmidt
Pharmaceuticals 2022, 15(7), 776; https://doi.org/10.3390/ph15070776 - 22 Jun 2022
Cited by 7 | Viewed by 2502
Abstract
Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. [...] Read more.
Leishmaniasis may occur in three different clinical forms, namely, visceral, mucocutaneous and cutaneous, which are caused by different species of trypanosomatid protozoans of the genus Leishmania. Pentavalent antimonials are the leading treatment for cutaneous leishmaniasis despite the hepatic, renal, and cardiac toxicity. In addition, the response of some Leishmania species to pentavalent antimonials is increasingly poorer, and therefore new and more potent therapeutic alternatives are needed. Arnica montana L., Asteraceae, is a traditional medicinal plant of Europe and preparations of its flowers are commonly used externally to treat disorders of the musculoskeletal system as well as superficial inflammatory conditions. Previous studies have shown that Arnica tincture (AT), an ethanolic extract prepared from the flowerheads of Arnica montana as well as isolated Arnica sesquiterpene lactones (STLs) have antileishmanial activity in vitro against L. donovani and L. infantum, as well as in vivo against L. braziliensis. In this work, we studied the in vitro cytotoxicity and antileishmanial activity of AT and STLs against both L. braziliensis and L. tropica. The in vivo therapeutic effect of AT was studied in hamsters with cutaneous Leishmaniasis (CL) caused by experimental infection with L. braziliensis and L. tropica. Furthermore, various semisolid Arnica preparations were also evaluated against L. braziliensis. The STLs and the AT possess a very high in vitro activity against both Leishmania species with median effective concentrations (EC50) ranging from 1.9 to 5.9 μg/mL. The AT was not cytotoxic for human tissue macrophages, skin fibroblasts, and hepatic cells. The therapeutic response of hamsters infected with L. braziliensis to the topical treatment with AT was 87.5% at a dose of 19.2 μg STL/2× day/60 d, 72.7% at doses of 19.2 μg STL/1× d/60 d and 67% at a dose of 38.4 μg STL/2× d/60 d. In turn, the therapeutic response in hamsters infected with L. tropica was 100% when treated at a dose of 19.2 μg STL/2× day/60 d and 71% at a dose of 38.4 μg STL/2× d/60 d. On the other hand, the effectiveness of treatment with glucantime administered intralesionally at a dose of 200 mg/every three days for 30 days was 62.5% for L. braziliensis and 37.5% for L. tropica infection. These results are promising and encourage the implementation of clinical trials with AT in CL patients as a first step to using AT as a drug against CL. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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Review

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56 pages, 12047 KiB  
Review
Over 40 Years of Fosmidomycin Drug Research: A Comprehensive Review and Future Opportunities
by Talea Knak, Mona A. Abdullaziz, Stefan Höfmann, Leandro A. Alves Avelar, Saskia Klein, Matthew Martin, Markus Fischer, Nobutada Tanaka and Thomas Kurz
Pharmaceuticals 2022, 15(12), 1553; https://doi.org/10.3390/ph15121553 - 14 Dec 2022
Cited by 15 | Viewed by 4756
Abstract
To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and [...] Read more.
To address the continued rise of multi-drug-resistant microorganisms, the development of novel drugs with new modes of action is urgently required. While humans biosynthesize the essential isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) via the established mevalonate pathway, pathogenic protozoa and certain pathogenic eubacteria use the less well-known methylerythritol phosphate pathway for this purpose. Important pathogens using the MEP pathway are, for example, Plasmodium falciparum, Mycobacterium tuberculosis, Pseudomonas aeruginosa and Escherichia coli. The enzymes of that pathway are targets for antiinfective drugs that are exempt from target-related toxicity. 2C-Methyl-D-erythritol 4-phosphate (MEP), the second enzyme of the non-mevalonate pathway, has been established as the molecular target of fosmidomycin, an antibiotic that has so far failed to be approved as an anti-infective drug. This review describes the development and anti-infective properties of a wide range of fosmidomycin derivatives synthesized over the last four decades. Here we discuss the DXR inhibitor pharmacophore, which comprises a metal-binding group, a phosphate or phosphonate moiety and a connecting linker. Furthermore, non-fosmidomycin-based DXRi, bisubstrate inhibitors and several prodrug concepts are described. A comprehensive structure–activity relationship (SAR) of nearly all inhibitor types is presented and some novel opportunities for further drug development of DXR inhibitors are discussed. Full article
(This article belongs to the Special Issue Drug Discovery and Evaluation for the Treatment of Parasitic Infections)
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