Cinnamoyl aryl hydrazones as potent leishmanicidal agents: design, synthesis, and structure-activity relationships

Parasitic diseases like leishmaniasis and Chagas pose significant global health challenges due to limited treatment options and drug resistance. In this study, a series of novel cinnamoyl aryl hydrazone derivatives was synthesized and tested against Leishmania donovani and Trypanosoma cruzi. Four compounds showed promising antileishmanial activity (from 1.27 to 19.53 μM), with two analogues displaying superior potency compared to some current first-line treatments, such as sodium stibogluconate and paromomycin. Computational analyses revealed that activity is driven by specific electronic properties rather than steric factors, while a methyl group consistently reduced potency. The compounds demonstrated favorable predicted ADME properties and were not flagged as aggregators. This research identifies cinnamoyl aryl hydrazones as a promising scaffold for leishmanicidal drug discovery, providing a rational basis for future optimization efforts.