Sustainable Modification of Minimolide: Influence of Structure and Acylation Pattern on Anti‐ <i>Trypanosoma cruzi</i> Activity

Minimolide, a sesquiterpene lactone isolated from Mikania minima, has displayed promising activity against Trypanosoma cruzi. The biocatalytic derivatization of minimolide and its analogs via selective acetylation and deacetylation is reported here using commercial lipases under mild and sustainable conditions. Reaction optimization identified Rhizomucor miehei lipase (RMIM) and Candida antarctica lipase B (CAL B) as the most efficient catalysts for acetylation and regioselective deacetylation, respectively. Structural transformations allow the synthesis of heliangolide and elemanolide analogs. The impact of the sesquiterpene lactone scaffold and acylation pattern on anti-Trypanosoma cruzi activity is evaluated in intracellular amastigotes. Compared to the parent compound, acetylated minimolide show enhanced antiparasitic activity (IC₅₀ = 1.08 µM) and a higher selectivity index (SI = 23.21). Likewise, acetylated heliangolide displayed improved selectivity as a result of reduced cytotoxicity. These findings underscore the usefulness of biocatalytic approaches in designing structurally optimized and more selective antitrypanosomal agents derived from natural lactones.