Synthesis and biological evaluation of pyridine-based derivatives as potential inhibitors of Leishmania major propagation.
8 affiliations
- 1Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre Dokki Cairo 12622 Egypt [email protected].
- 2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University Alexandria 21521 Egypt.
- 3Pharmacy Program, Allied Health Department, College of Health and Sport Sciences, University of Bahrain P. O. Box 32038 Bahrain.
- 4Pesticide Chemistry Department, Chemical Industries Research Institute, National Research Centre Cairo 12622 Egypt.
- 5Laboratory of Pharmacology & Pharmacotherapeutics, College of Pharmaceutical Sciences, Ritsumeikan University Kusatsu Shiga Japan.
- 6Pediatric Department, Faculty of Medicine, Cairo University Cairo Egypt.
- 7Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University Kafr El Sheikh 33516 Egypt [email protected].
- 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alsalam University Tanta 31511 Egypt.
Abstract
Leishmaniasis is a neglected tropical disease for which current treatment options remain severely limited and associated with considerable toxicity, underscoring the urgent need for novel therapeutic agents with innovative chemical structures. To address this gap, we designed, synthesized, and tested a series of fourteen hybrid molecules (3a-g and 5a-g) that combine a pyridine core with either thiosemicarbazone or thiazolidinone functionalities, and evaluated their activity against Leishmania major in vitro. Among these, the pyridine-thiazolidinone hybrids (5a-g) demonstrated numerically better efficacy compared to their pyridine-thiosemicarbazone counterparts (3a-g). Significantly, compound 5e emerged as a promising dual-stage agent, demonstrated to be effective against both promastigote forms (IC₅₀ = 8.42 ± 0.14 µM), which is comparable to the reference drug miltefosine (IC₅₀ = 7.83 µM), and axenic amastigotes forms (IC₅₀ = 8.88 ± 0.16 µM), similarly aligned with the activity of miltefosine (IC₅₀ = 8.07 µM). Mechanistic exploration via a folate-reversal assay pointed to an antifolate mode of action, proposed, modeling-supported target enzymes DHFR-TS and PTR1. Parasite viability was restored in a dose-responsive manner when co-administered with folic or folinic acid, with recovery rates reaching up to 74% at 20 µM and 83% at 100 µM folic acid, depending on the compound assessed. Additionally, 5e exhibited a favorable in vitro cytotoxicity profile in VERO cells (CC₅₀ = 393.04 µM; selectivity index = 46.63). To gain further insight, molecular docking and 100 ns molecular dynamics (MD) simulations were carried out to explore the possible binding interactions and dynamic stability of 5e within the PTR1 active site. These computational analyses support the compound's proposed inhibitory capacity against Lm-PTR1. Collectively, our results introduce a promising new class of antileishmanial agents that act through selective disruption of the folate biosynthesis pathway, highlighting their considerable therapeutic promise in the fight against leishmaniasis.
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BibTeX
@article{sabt2026synthesis,
title = {{Synthesis and biological evaluation of pyridine-based derivatives as potential inhibitors of Leishmania major propagation.}},
author = {Ahmed Sabt and Adnan A Bekhit and Hanaa Farag and Huda Jawad and Kikuko Amagase and Hoda Atef Abdelsattar Ibrahim and Tamer M Ibrahim and Abdelsamed I Elshamy and Moataz A Shaldam and Wagdy M Eldehna},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra07150c},
url = {https://europepmc.org/article/MED/42936256},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Synthesis and biological evaluation of pyridine-based derivatives as potential inhibitors of Leishmania major propagation.
AU - Ahmed Sabt
AU - Adnan A Bekhit
AU - Hanaa Farag
AU - Huda Jawad
AU - Kikuko Amagase
AU - Hoda Atef Abdelsattar Ibrahim
AU - Tamer M Ibrahim
AU - Abdelsamed I Elshamy
AU - Moataz A Shaldam
AU - Wagdy M Eldehna
PY - 2026
DA - 2026/10/26
JO - RSC advances
DO - 10.1039/d6ra07150c
UR - https://europepmc.org/article/MED/42936256
AB - Leishmaniasis is a neglected tropical disease for which current treatment options remain severely limited and associated with considerable toxicity, underscoring the urgent need for novel therapeutic agents with innovative chemical structures. To address this gap, we designed, synthesized, and tested a series of fourteen hybrid molecules (3a-g and 5a-g) that combine a pyridine core with either thiosemicarbazone or thiazolidinone functionalities, and evaluated their activity against Leishmania major in vitro. Among these, the pyridine-thiazolidinone hybrids (5a-g) demonstrated numerically better efficacy compared to their pyridine-thiosemicarbazone counterparts (3a-g). Significantly, compound 5e emerged as a promising dual-stage agent, demonstrated to be effective against both promastigote forms (IC₅₀ = 8.42 ± 0.14 µM), which is comparable to the reference drug miltefosine (IC₅₀ = 7.83 µM), and axenic amastigotes forms (IC₅₀ = 8.88 ± 0.16 µM), similarly aligned with the activity of miltefosine (IC₅₀ = 8.07 µM). Mechanistic exploration via a folate-reversal assay pointed to an antifolate mode of action, proposed, modeling-supported target enzymes DHFR-TS and PTR1. Parasite viability was restored in a dose-responsive manner when co-administered with folic or folinic acid, with recovery rates reaching up to 74% at 20 µM and 83% at 100 µM folic acid, depending on the compound assessed. Additionally, 5e exhibited a favorable in vitro cytotoxicity profile in VERO cells (CC₅₀ = 393.04 µM; selectivity index = 46.63). To gain further insight, molecular docking and 100 ns molecular dynamics (MD) simulations were carried out to explore the possible binding interactions and dynamic stability of 5e within the PTR1 active site. These computational analyses support the compound's proposed inhibitory capacity against Lm-PTR1. Collectively, our results introduce a promising new class of antileishmanial agents that act through selective disruption of the folate biosynthesis pathway, highlighting their considerable therapeutic promise in the fight against leishmaniasis.
SN - 2046-2069
ER -