Design, synthesis, and antileishmanial evaluation of linker-diversified trimethoxyphenyl-1,2,4-triazole derivatives as folate pathway inhibitors of <i>Leishmania major</i>.

Abstract

Leishmaniasis remains a life-threatening neglected tropical disease with a critically limited therapeutic arsenal, where resistance, toxicity, and the absence of an approved vaccine collectively underscore the urgent need for novel antileishmanial agents. Targeting the folate biosynthetic pathway, specifically the Leishmania -essential enzymes dihydrofolate reductase-thymidylate synthase (DHFR-TS) and pteridine reductase 1 (PTR1), represents a mechanistically validated and resistance-resilient strategy. Herein, we report the design, synthesis, and comprehensive biological evaluation of 19 triazole-based compounds (11a-b, 12a-f, 15a-i, 16a-b) incorporating the 3,4,5-trimethoxyphenyl pharmacophore, a structural mimic of trimethoprim's antifolate motif, within a positionally isomeric 1,2,4-triazole scaffold, with systematic linker diversification yielding diacylhydrazide, acyl(thio)semicarbazide, and acylhydrazone series. Biological profiling against Leishmania major ( Lm ) revealed that diacylhydrazide and acyl(thio)semicarbazide derivatives showed approximately 2-fold greater in vitro potency than miltefosine against both promastigote and amastigote stages. Folate rescue assays implicated PTR1-prominent inhibition, corroborated by molecular docking against LmPTR1 . Cytotoxicity profiling identified 11b and 12c as preferred leads, with selectivity indices approximately 12-fold greater than miltefosine.

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