Piperidine-based small molecules as dual-stage antileishmanial agents targeting parasite folate pathway

As specific antileishmanial agents, we provide a structurally varied library of recently synthesized piperidine-based small molecules (7a-h, 12a-c, and 14a-b). When tested against Leishmania major promastigotes and intracellular amastigotes, they outperformed the reference medication, miltefosine, with IC₅₀ values ranging from 0.54 to 4.00 μM for promastigotes and from 0.62 to 5.86 μM for amastigotes. The compounds with the highest selectivity indices were 7 f, 7 h, 12c, and 14a; they combined potent compounds with acceptable cytotoxicity. In vitro evaluation of folate-pathway inhibition, expressed through the percentage survival assay, indicated that the tested compounds interfere with folate-dependent biochemical processes. Given the central role of pteridine reductase 1 (PTR1) in the folate and pteridine metabolic pathways, molecular docking was subsequently performed on PTR1 to explore a possible mechanistic link. The docking results revealed stable, favorable interactions within the PTR1 active site, supporting the plausibility of PTR1 involvement and highlighting this scaffold as a promising chemotype for the development of selective antileishmanial agents.