Anti-Trypanosoma cruzi Effects of Sesquiterpenoids from Branches of Drimys brasiliensis (Winteraceae).

The hexane extract of Drimys brasiliensis (Winteraceae) branches displayed activity against trypomastigote forms of Trypanosoma cruzi and was subjected to a bioactivity-guided fractionation procedures to afford four bisabolenerel-(3S,7R)-3-hydroxy-bisabola-1-(6),10-dien-2-one (1), rel-(2S,3S,7R)-bisabola-1-(6),10-diene-2,3-diol (2), rel-(3S,6R,7R)-3,6-epidioxy-1,10-bisaboladiene (3), and α-curcumene (4)as well as two drimanepolygodial (5), and 9-deoxymuzigadial (6)type sesquiterpenes. This is the first report of compounds 1 and 2 as natural products. Compounds 1-6 showed promising activity against trypomastigotes and intracellular amastigotes with EC50 values ranging from 3.8 to 88.3 μM and 3.1 to 24.2 μM, respectively. Furthermore, the isolated compounds displayed no cytotoxicity for mammalian fibroblasts (CC50 > 200 μM), demonstrating a safety profile. In silico studies of bioactive sesquiterpenes showed adequate predictions for drug-like properties, with adherence to Lipinski's rules of five (RO5), acceptable ADMET properties and no similarities to interference compounds (PAINS). Finally, an in silico molecular docking exercise suggested that the more active compounds 5 and 6 could interact favorably with the T. cruzi mitochondrial ATP synthase protein. Altogether, these findings highlight the potential of bisabolane and drimane type sesquiterpenoids isolated from branches of D. brasiliensis as new hit compounds and contribute to the ongoing search for novel molecular scaffolds for the treatment of a neglected tropical disease such as Chagas disease.