Design, Synthesis, and Repurposing of Rosmarinic Acid-β-Amino-α-Ketoamide Hybrids as Antileishmanial Agents.

A series of rosmarinic acid-β-amino-α-ketoamide hybrids were synthesized and rationally repurposed towards the identification of new antileishmanial hit compounds. Two hybrids, and showed promising activity (IC values of 9.5 and 8.8 μM against promastigotes, respectively). Their activities were comparable to erufosine. In addition, cytotoxicity evaluation employing human THP-1 cells revealed that the two hybrids and possess no cytotoxic effects up to 100 µM, while erufosine possessed cytotoxicity with CC value of 19.4 µM. In silico docking provided insights into structure-activity relationship emphasizing the importance of the aliphatic chain at the α-carbon of the cinnamoyl carbonyl group establishing favorable binding interactions with CALP and ARG in both hybrids and . In light of these findings, hybrids and are suggested as potential safe antileishmanial hit compounds for further development of anti-leishmanial agents.