Onnamides and a Novel Analogue, Onnamide G, as Potent Leishmanicidal Agents

Leishmaniasis is a neglected tropical disease posing significant global health challenges. Given the limited effective treatment options and associated constraints, many patients are unable to complete therapy. In this study, we report the remarkable leishmanicidal activity of onnamides derived from the marine sponge Theonella sp. against the promastigote form of Leishmania major (IC₅₀ = 0.2-140 nM) and demonstrate their selectivity through cytotoxicity assessments on human hepatoma HepG2 cells. Structural-activity relationship (SAR) analyses were conducted using 6,7-dihydro-onnamide A and its analogs. Furthermore, we compared the action mechanisms of amphotericin B, the primary drug currently used for treatment, and the obtained onnamides. Based on biological evaluations and SAR studies, onnamides can be considered promising candidates for anti-leishmanial chemotherapy, warranting further investigation.