Annonaceae Terpenoids as Potential Leishmanicidal Agents

Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania . Current drug treatments for leishmaniasis are outdated and questionable due to variability in their effectiveness between different Leishmania species. In this perspective, we combined two predictive ligand-based virtual screening models to select potentially active molecules against Leishmania amazonensis from specialized metabolites of Annonaceae. To construct the predictive models, compounds with known activity for L. amazonensis were selected from the ChEMBL database and subdivided into L. amazonensis protozoal, amastigote, and promastigote datasets. Our models obtained an accuracy of 63% for the amastigote and 81% for the promastigote form, enabling ligand-based virtual screening of the Annonaceae databank. We performed a consensus analysis between the two models to select 16 substances to undergo in vitro testing against the promastigote form of L. amazonensis . Four substances, namely lupeol, morolic acid, lithocholic acid, and xylodiol, showed leishmanicidal activity. The triterpene lupeol showed the best activity in in silico and in vitro biological assays. The predicted activity against the amastigote form of Leishmania amazonensis exceeds 77% for lupeol, morolic acid, and lithocholic acid. The hits proposed here could serve as a promising starting point for the development of new natural products–based leishmanicidal therapeutical agents. Graphical Abstract