TTAS a New Stilbene Derivative that Induces Apoptosis in Leishmania Infantum

Leishmania parasites are able to undergo apoptosis (programmed cell death), similarly to mammalian cells. Recently it was demonstrated in vitro the anti-leishmanial effect of some natural and synthetic stilbenoids including resveratrol and piceatannol. In this study we evaluated the Leishmanicidal activity of a pool of stilbene derivatives which had previously shown high apoptotic efficacy against neoplastic cells. All the compounds tested were capable to decrease the parasite viability in a dose-dependent manner. Trans-stilbenes proved to be markedly more effective than cis-isomers. This was different from that observed in tumor cells in which cis-stilbenes were more potent cytotoxic agents. Trans-3,4',5-trimethoxy-3'-amino-stilbene (TTAS) was the most active stilbene showing in Leishmania infantum a LD50 value of 2.6 µg/mL. In contrast TTAS showed a low toxicity when tested on normal hemopoietic cells. This compound induced apoptosis in parasites by disrupting the mitochondrial membrane potential. Moreover it shows the ability to block Leishmania parasites in G2-M phase of cell cycle in agreement with the data obtained by affinity chromatography that identify tubulin as the putative target of TTAS. In conclusion, our results indicate that some stilbene derivatives are highly effective as anti-leishmanial agents and TTAS represents a pro-apoptotic agent in Leishmania parasites that merit further in vivo investigation.