An exploration of potent antileishmanial agents derived from quinoline–thiazole and thiadiazole hybrids, targeting DHFR-TS and PTR1: design, synthesis, and computational analyses

an antifolate mechanism, selectively inhibiting key enzymes in the folate pathway: pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and 100 ns molecular dynamics (MD) simulations demonstrated that the quinoline core occupies a hydrophobic pocket formed by residues Phe113, Leu188, Leu226, and Leu229, engaging in stable hydrophobic interactions and π-π stacking with Phe113. Furthermore, the quinoline scaffold and hydrazinecarbodithioate moiety formed hydrogen bonds with Tyr194, Gly225, and His241, reinforcing binding stability. Our findings introduce a promising new class of antileishmanial agents that disrupt the folate biosynthesis pathway, offering significant therapeutic potential for combating leishmaniasis.