Anti- <i>Trypanosoma cruzi</i> Effects of Sesquiterpenoids from Branches of <i>Drimys brasiliensis</i> (Winteraceae)

The hexane extract of <i>Drimys brasiliensis</i> (Winteraceae) branches displayed activity against trypomastigote forms of <i>Trypanosoma cruzi</i> and was subjected to a bioactivity-guided fractionation procedures to afford four bisabolene<i>rel</i>-(3<i>S</i>,7<i>R</i>)-3-hydroxy-bisabola-1-(6),10-dien-2-one (<b>1</b>), <i>rel</i>-(2<i>S</i>,3<i>S</i>,7<i>R</i>)-bisabola-1-(6),10-diene-2,3-diol (<b>2</b>), <i>rel</i>-(3<i>S</i>,6<i>R</i>,7<i>R</i>)-3,6-epidioxy-1,10-bisaboladiene (<b>3</b>), and α-curcumene (<b>4</b>)as well as two drimanepolygodial (<b>5</b>), and 9-deoxymuzigadial (<b>6</b>)type sesquiterpenes. This is the first report of compounds <b>1</b> and <b>2</b> as natural products. Compounds <b>1-6</b> 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. <i>In silico</i> 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 <i>in silico</i> molecular docking exercise suggested that the more active compounds <b>5</b> and <b>6</b> could interact favorably with the <i>T. cruzi</i> mitochondrial ATP synthase protein. Altogether, these findings highlight the potential of bisabolane and drimane type sesquiterpenoids isolated from branches of <i>D. brasiliensis</i> 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.