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Pharmaceuticals
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Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases
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Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases

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

Deadline for manuscript submissions: 27 July 2026 | Viewed by 6313

Special Issue Editors

Dr. Juliana Mesquita

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Guest Editor
Department of Parasitology, Institute of Biomedical Sciences of the University of São Paulo, São Paulo, Brazil
Interests: leishmaniasis; drug discovery; drug combinations; drug activity; neglected tropical diseases
Dr. Juliana Quero Reimão

E-Mail Website
Guest Editor
Laboratory of Preclinical Assays and Research of Alternative Sources of Innovative Therapy for Toxoplasmosis and Other Sicknesses (PARASITTOS), Departamento de Morfologia e Patologia Básica, Faculdade de Medicina de Jundiaí, Jundiaí 13202-550, Brazil
Interests: leishmaniasis; toxoplasmosis; drug discovery; drug screening; pre-clinical assays
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neglected Tropical Diseases (NTDs) affect over a billion people globally, disproportionately impacting underserved populations. Despite their burden, these diseases remain underexplored in drug discovery pipelines. This Special Issue, Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases, seeks to spotlight innovative research aimed at bridging this gap. We welcome original research articles and reviews focused on identifying and characterizing novel drug targets, the discovery of promising drug candidates, and advancements in assay development tailored to NTDs. Topics of interest include, but are not limited to:

  • Molecular and cellular mechanisms underlying NTDs.
  • High-throughput screening platforms for drug discovery.
  • Development and validation of target-based and phenotypic assays.
  • Studies on structure-activity relationships and lead optimization.
  • Preclinical evaluations of novel compounds.
  • Insights into drug resistance mechanisms and strategies to overcome them.

By gathering cutting-edge research, this Special Issue aims to accelerate the identification of safe and effective therapeutics for diseases such as leishmaniasis, Chagas disease, schistosomiasis, and others.

Dr. Juliana Tonini Mesquita
Dr. Juliana Quero Reimão
Guest Editors

Manuscript Submission Information

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 250 words) can be sent to the Editorial Office for assessment.

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

  • neglected tropical diseases
  • leishmaniasis
  • chagas disease

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Published Papers (5 papers)

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Research

14 pages, 3287 KB  
Article
Econazole Exhibits In Vitro and In Vivo Efficacy Against Leishmania amazonensis
by Juliana Tonini Mesquita, Ingrid de Oliveira Dias, Andre Gustavo Tempone and Juliana Quero Reimão
Pharmaceuticals 2026, 19(1), 185; https://doi.org/10.3390/ph19010185 - 21 Jan 2026
Viewed by 680
Abstract
Background/Objectives: Cutaneous leishmaniasis (CL) remains a major neglected tropical disease, and current chemotherapeutic options are limited by toxicity and emerging resistance. Repurposing azole antifungals is a promising approach, as they target ergosterol biosynthesis, a pathway also essential in Leishmania spp. This study investigated [...] Read more.
Background/Objectives: Cutaneous leishmaniasis (CL) remains a major neglected tropical disease, and current chemotherapeutic options are limited by toxicity and emerging resistance. Repurposing azole antifungals is a promising approach, as they target ergosterol biosynthesis, a pathway also essential in Leishmania spp. This study investigated the antileishmanial potential of econazole through in vitro and in vivo assays. Methods: Econazole activity was evaluated against Leishmania amazonensis promastigotes and intracellular amastigotes using MTT and luminescence-based methods. Cytotoxicity in NCTC cells was determined to calculate the selectivity index (SI). Drug interactions with miltefosine were assessed by fixed-ratio isobologram analysis. In vivo efficacy was examined in BALB/c mice infected with L. amazonensis and orally treated with econazole (2.5, 5, or 10 mg/kg/day) for 28 days. Lesion development and parasite burden were monitored. Molecular docking simulations were performed using SwissDock. Results: Econazole showed potent in vitro activity, with EC50 values of 8.9 µM for promastigotes and 11 µM for intracellular amastigotes, and a CC50 of 31 µM. Isobologram analysis revealed additive interactions with miltefosine (ΣFIC 0.5–1.2; mean 0.95). In vivo, econazole reduced lesion size and parasite load, achieving up to 75% reduction at 10 mg/kg/day. Docking results suggested that econazole may inhibit sterol biosynthesis, potentially through interaction with 14α-demethylase. Conclusions: These findings provide the first evidence of econazole activity against L. amazonensis in vitro and in vivo. Its exploratory efficacy and compatibility with miltefosine support further investigation of econazole as a repurposed candidate for CL, including optimization of dosing strategies and combination regimens. Full article
(This article belongs to the Special Issue Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases)
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32 pages, 2940 KB  
Article
Integrated In Vitro and In Silico Profiling of Piperazinyl Thiosemicarbazone Derivatives Against Trypanosoma cruzi: Stage-Specific Activity and Enzyme Inhibition
by Héctor A. Baldoni, María L. Sbaraglini, Darío E. Balcazar, Diego G. Arias, Sergio A. Guerrero, Catalina D. Alba Soto, Wioleta Cieslik, Marta Rogalska, Jaroslaw Polański, Ricardo D. Enriz, Josef Jampilek and Robert Musiol
Pharmaceuticals 2026, 19(1), 182; https://doi.org/10.3390/ph19010182 - 20 Jan 2026
Viewed by 1007
Abstract
Background: Trypanosoma cruzi, the causative agent of Chagas disease, remains a major public health concern, and there is a continued need for new antitrypanosomal agents. Thiosemicarbazone (TSC) derivatives have emerged as a promising class of compounds with potential antiparasitic activity. Objectives: [...] Read more.
Background: Trypanosoma cruzi, the causative agent of Chagas disease, remains a major public health concern, and there is a continued need for new antitrypanosomal agents. Thiosemicarbazone (TSC) derivatives have emerged as a promising class of compounds with potential antiparasitic activity. Objectives: This study aimed to report the synthesis, characterization, and biological profiling of a novel series of thiosemicarbazone derivatives as antitrypanosomal agents against Trypanosoma cruzi. Methods: Fourteen new compounds and six previously described analogues were prepared and characterized by 1H/13C nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). As a preliminary in vitro screen, activity was assessed by direct parasite counting in epimastigote and bloodstream trypomastigote forms, as tractable models of replicative and infective stages sharing core metabolic targets with intracellular amastigotes. Epimastigote potency was quantified as half-maximal effective concentrations (EC50) derived from dose–response curves, whereas trypomastigote response was evaluated as percent viability after treatment at a fixed concentration of 20 µM. Mechanistic profiling included inhibition assays against the cysteine protease cruzipain (CZP) and selected redox defense enzymes, complemented by in silico similarity clustering and binding-pose affinity scoring. Results: A nitro-methoxy-substituted TSC showed potent CZP inhibition but limited trypomastigote efficacy, whereas brominated analogues displayed dual-stage activity independent of CZP inhibition. Tanimoto similarity analysis identified distinct structure–activity clusters, linking nitro-methoxy substitution to epimastigote selectivity and brominated scaffolds to broader antiparasitic profiles, with hydrophobicity and steric complementarity as key determinants. Enzymatic assays revealed no significant inhibition of cytosolic tryparedoxin peroxidase (cTXNPx) or glutathione peroxidase type I (TcGPx-I), suggesting redox disruption is not a primary mode of action. In vitro and in silico analyses showed low or no non-specific cytotoxicity under the tested conditions, supporting further optimization of these derivatives as antitrypanosomal preliminary hits. Key hits included derivative 3e (epimastigote EC50 = 0.36 ± 0.02 µM) and brominated analogues 2c and 2e (epimastigote EC50 = 3.92 ± 0.13 and 4.36 ± 0.10 µM, respectively), while docking supported favorable binding-pose affinity (e.g., ΔGS-pose = −20.78 ± 2.47 kcal/mol for 3e). Conclusions: These results support further optimization of the identified thiosemicarbazone derivatives as preliminary antitrypanosomal hits and provide insight into structure–activity relationships and potential mechanisms of action. Full article
(This article belongs to the Special Issue Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases)
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14 pages, 1470 KB  
Article
Coffea arabica Extracts and Metabolites with Potential Inhibitory Activity of the Major Enzymes in Bothrops asper Venom
by Erika Páez, Yeisson Galvis-Pérez, Jaime Andrés Pereañez, Lina María Preciado and Isabel Cristina Henao-Castañeda
Pharmaceuticals 2025, 18(8), 1151; https://doi.org/10.3390/ph18081151 - 1 Aug 2025
Cited by 1 | Viewed by 1168
Abstract
Background/Objectives: Most snakebite incidents in Latin America are caused by species of the Bothrops genus. Their venom induces severe local effects, against which antivenom therapy has limited efficacy. Metabolites derived from Coffea arabica have demonstrated anti-inflammatory and anticoagulant properties, suggesting their potential [...] Read more.
Background/Objectives: Most snakebite incidents in Latin America are caused by species of the Bothrops genus. Their venom induces severe local effects, against which antivenom therapy has limited efficacy. Metabolites derived from Coffea arabica have demonstrated anti-inflammatory and anticoagulant properties, suggesting their potential as therapeutic agents to inhibit the local effects induced by B. asper venom. Methods: Three enzymatic assays were performed: inhibition of the procoagulant and amidolytic activities of snake venom serine proteinases (SVSPs); inhibition of the proteolytic activity of snake venom metalloproteinases (SVMPs); and inhibition of the catalytic activity of snake venom phospholipases A2 (PLA2s). Additionally, molecular docking studies were conducted to propose potential inhibitory mechanisms of the metabolites chlorogenic acid, caffeine, and caffeic acid. Results: Green and roasted coffee extracts partially inhibited the enzymatic activity of SVSPs and SVMPs. Notably, the green coffee extract, at a 1:20 ratio, effectively inhibited PLA2 activity. Among the individual metabolites tested, partial inhibition of SVSP and PLA2 activities was observed, whereas no significant inhibition of SVMP proteolytic activity was detected. Chlorogenic acid was the most effective metabolite, significantly prolonging plasma coagulation time and achieving up to 82% inhibition at a concentration of 62.5 μM. Molecular docking analysis revealed interactions between chlorogenic acid and key active site residues of SVSP and PLA2 enzymes from B. asper venom. Conclusions: The roasted coffee extract demonstrated the highest inhibitory effect on venom toxins, potentially due to the formation of bioactive compounds during the Maillard reaction. Molecular modeling suggests that the tested inhibitors may bind to and occupy the substrate-binding clefts of the target enzymes. These findings support further in vivo research to explore the use of plant-derived polyphenols as adjuvant therapies in the treatment of snakebite envenoming. Full article
(This article belongs to the Special Issue Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases)
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13 pages, 1388 KB  
Article
Indazole Derivatives Against Murine Cutaneous Leishmaniasis
by Niurka Mollineda-Diogo, Yunierkis Pérez-Castillo, Sergio Sifontes-Rodríguez, Osmani Marrero-Chang, Alfredo Meneses-Marcel, Alma Reyna Escalona-Montaño, María Magdalena Aguirre-García, Teresa Espinosa-Buitrago, Yeny Morales-Moreno and Vicente Arán-Redó
Pharmaceuticals 2025, 18(8), 1107; https://doi.org/10.3390/ph18081107 - 25 Jul 2025
Viewed by 1130
Abstract
Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side [...] Read more.
Background/Objectives: Leishmaniasis is a zoonotic and anthropozoonotic disease with significant public health impact worldwide and is classified as a neglected tropical disease. The search for new affordable treatments, particularly oral and/or topical ones that are easy to administer and have fewer side effects, remains a priority for the scientific community in this field of research. In previous investigations, 3-alkoxy-1-benzyl-5-nitroindazole derivatives showed remarkable in vitro results against Leishmania species, and predictions of absorption, distribution, metabolism, excretion, and toxicity properties, as well as pharmacological scores, of the compounds classified as active were superior to those of amphotericin B, indicating their potential as candidates for in vivo studies. Therefore, the aim of the present study was to evaluate the in vivo antileishmanial activity of the indazole derivatives NV6 and NV16. Methods: The compounds were administered intralesionally at concentrations of 10 and 5 mg/kg in a BALB/c mouse model of cutaneous leishmaniasis caused by Leishmania amazonensis. To evaluate the efficacy of the compounds, indicators such as lesion size, ulcer area, lesion weight, and parasitic load were determined. Amphotericin B was used as a positive control. Results: The compound NV6 showed leishmanicidal activity comparable to that observed with amphotericin B, with a significant reduction in lesion development and parasite load, while NV16 caused a reduction in ulcer area. Conclusions: These results provide strong evidence for the antileishmanial activity of NV6 and support future studies to improve its pharmacokinetic profile, as well as the investigation of combination therapies with other chemotherapeutic agents currently in use. Full article
(This article belongs to the Special Issue Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases)
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17 pages, 3491 KB  
Article
Discovery of Novel CRK12 Inhibitors for the Treatment of Human African Trypanosomiasis: An Integrated Computational and Experimental Approach
by Qin Li, Jiayi Luo, Chenggong Fu, Wenqingqing Kang, Lingling Wang, Henry Tong, Zhaorong Lun, Qianqian Zhang, Dehua Lai and Huanxiang Liu
Pharmaceuticals 2025, 18(6), 778; https://doi.org/10.3390/ph18060778 - 23 May 2025
Cited by 1 | Viewed by 1541
Abstract
Background: Human African trypanosomiasis (HAT), caused by Trypanosoma brucei, is a neglected tropical disease with limited treatments, highlighting the pressing need for new drugs. Cell division cycle-2-related kinase 12 (CRK12), a pivotal protein involved in the cell cycle regulation of T. brucei [...] Read more.
Background: Human African trypanosomiasis (HAT), caused by Trypanosoma brucei, is a neglected tropical disease with limited treatments, highlighting the pressing need for new drugs. Cell division cycle-2-related kinase 12 (CRK12), a pivotal protein involved in the cell cycle regulation of T. brucei, has emerged as a promising therapeutic target for HAT, yet effective CRK12 inhibitors remain lacking. Methods: An integrated strategy combining computational modeling, virtual screening, molecular dynamics (MD) simulations, and experimental validation was adopted to discover potential inhibitors against CRK12. By using the predicted and refined 3D structure of CRK12 from AlphaFold2 and MD simulation, over 1.5 million compounds were screened based on multiple-scale molecular docking, and 26 compounds were selected for evaluation of biological activity based on anti-T. brucei bioassays. Dose–response curves were generated for the most potent inhibitors, and the interaction mechanism between the top four compounds and CRK12 was explored by MD simulations and MM/GBSA binding free energy analysis. Results: Of the 26 compounds, six compounds demonstrated sub-micromolar to low-micromolar IC50 values (0.85–3.50 µM). The top four hits, F733-0072, F733-0407, L368-0556, and L439-0038, exhibited IC50 values of 1.11, 1.97, 0.85, and 1.66 µM, respectively. Binding free energy and energy decomposition analyses identified ILE335, VAL343, PHE430, ALA433, and LEU482 as hotspot residues for compound binding. Hydrogen bonding analysis demonstrated that these compounds can form stable hydrogen bonds with the hinge residue ALA433, ensuring their stable binding within the active site. Conclusions: This study establishes a robust and cost-effective pipeline for CRK12 inhibitor discovery, identifying several novel inhibitors demonstrating promising anti-HAT activity. The newly discovered scaffolds exhibit structural diversity distinct from known CRK12 inhibitors, providing valuable lead compounds for anti-trypanosomal drug development. Full article
(This article belongs to the Special Issue Novel Drug Targets and Drug Candidates for Neglected Tropical Diseases)
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