Identification of potential antileishmanial 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-ones, in vitro metabolic stability, cytotoxicity and molecular modeling studies

We report the synthesis and in vitro evaluation of 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives against Leishmania donovani. Amongst the compound library synthesized, molecules 3d, 3f, 3h, 3i, 3l, and 3m demonstrated substantial dose-dependent killing of the promastigotes. Their IC50 values range from 55.0 to 77.0 μg/ml, with 3m (IC50 55.75 μg/ml) being equipotent with amphotericin B (IC50 50.0 μg/ml, used as standard). The most active compound 3m, is metabolically stable in rat liver microsomes. Furthermore, the molecules are highly specific against leishmania as shown by their weak antibacterial and antifungal activity. In vitro cytotoxicity studies show the compounds lack any cytotoxicity. Furthermore, molecular modeling studies show plausibility of binding to Leishmania donovani topoisomerase 1 (LdTop1). Structure activity relationships reveal bulky substitutions on the pyridone nitrogen are well-tolerated, and such compounds have better binding affinity. Intramolecular hydrogen bonds confer some rigidity to the molecules, rendering a degree of planarity akin to topotecan. Taken together, we emphasis the merits of molecules possessing the 1,3-disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one skeleton as potential antileishmanial agents warranting further investigation. [Display omitted] •1,3-Disubstituted-4-hydroxy-6-methylpyridin-2(1H)-one derivatives were screened against Leishmania donovani.•Antibacterial and antifungal activity was carried out to gauge the selectivity of compounds towards Leishmania spp.•Cytotoxicity study on HEK (human embryonic kidney) 293 cell lines indicate the compounds to be non-toxic.•Metabolic stability studies on rat liver microsomes exhibit the most active compounds to be stable.•Molecular modelling studies suggest Leishmania donovani topoisomerase 1 (LdTop1) to be a potential target.