Design, synthesis and biological activity of peptidyl β-nitrostyrenes as cysteine protease inhibitors against Leishmania donovani.

Cysteine proteases are essential for the survival of Leishmania parasites that cause several clinical forms of leishmaniases. Inhibiting cysteine protease can be a promising strategy against parasitic diseases because of their essential functions in the life cycles of these pathogens. The aim of the present study was to synthesize and evaluate peptidyl -nitrostyrenes as antipromastigote inhibitors against Leishmania donovani promastigotes. A library of 12 peptidyl β-nitrostyrenes was synthesized and evaluated for anti-promastigote activity. Most of the compounds exhibited comparable activity to the standard, with IC(50) values ranging from 1.468 to 16.81 μM. Notably, compounds 14a, 14e, 14f, and 14g showed significant activity against both L. donovani promastigotes and intracellular amastigotes. Compounds 14e and 14f displayed superior anti-promastigote activity with IC(50) values of 1.468 μM and 1.551 μM, respectively, compared to the standard (IC(50) = 3.073 μM). Moreover, compounds 14e and 14f demonstrated better inhibitory potential against intracellular amastigotes, with IC(50) values of 1.28 μM and 0.64 μM, respectively, outperforming AmphoB (IC(50) = 3.07 μM). Additionally, compounds 14a and 14g showed negligible cytotoxicity to mammalian macrophages even at a concentration of 28 μM. Given their high activity, favorable safety profiles, and cost-effective synthesis, this class of compounds holds promise for the development of anti-leishmanial drugs.