Pyridine-2,6-dicarboxylic acid derivatives of potential antileishmanial activity: synthesis, biological evaluation, and in-silico studies.

Leishmaniasis is a parasitic disease caused by Leishmania species, transmitted by infected sandflies. It remains a major health challenge in tropical and subtropical regions, with high morbidity and mortality. Current treatments, such as miltefosine, are limited by toxicity, resistance, and poor accessibility, highlighting the need for safer, more effective alternatives. This study reports the synthesis and characterization of pyridine-2,6-dicarboxylic acid derivatives, their antileishmanial activities, and suggested mechanisms of action. The synthetic method afforded sufficient yields and purities, making these compounds attractive for further study. Structures were confirmed by spectroscopic methods and elemental analyses. In-vitro evaluation against promastigote and amastigote forms of L. major showed that all compounds exhibited activity, with compound 4 being the most potent, displaying IC50 values of 2.86 ± 0.14 μM and 3.84 ± 0.16 μM, respectively, nearly three times more effective than miltefosine. Molecular docking indicated folate pathway inhibition, with compound 4 fitting well with Lm-PTR1. Cytotoxicity tests revealed a superior safety profile (IS = 108.2), significantly better than miltefosine. In-silico ADMET predictions supported favorable bioavailability and safety. These findings suggest that pyridine-2,6-dicarboxylic acid derivatives, particularly compound 4, represent promising candidates for future anti-leishmanial drug development.