Computational and experimental studies to discover a promising lead compound, chemically related to natural acetylene acetogenins from Porcelia macrocarpa, against amastigotes of Leishmania (L.) infantum.

Previous studies of the natural acetylenic acetogenin (2S,3R,4R)-3-hydroxy-4-methyl-2-(eicos-11'-yn-19'-enyl)butanolide (1), isolated from the plant Porcelia macrocarpa, indicated its in vitro activity against the clinically relevant form of Leishmania (L.) infantum, the intracellular amastigotes and no mammalian cytotoxicity. A second chemically related acetogenin, (2S,3R,4R)-3-hydroxy-4-methyl-2-(eicos-11'-ynyl) butanolide (2), exhibited a lack of antileishmanial activity at the highest tested concentration of 150 µM. These results suggest that the terminal double bond plays a crucial role in the antileishmanial activity of these compounds. Using a computational protocol to predict the metabolism of 1, the 19'-oxirane-derivative (3) was proposed, prepared, and experimentally tested against Leishmania (L.) infantum amastigotes. Compound 3 presented twofold more potency than 1, with an EC₅₀ value of 11.3 µM. Compounds 1-3 were also analyzed via molecular docking against L. (L.) infantum trypanothione reductase (TR) and thiol-dependent reductase 1 (TDR1), showing that the natural products 1 and 2 prefer specific regions in the active sites for lactone positioning. Docking of derivative 3 revealed interaction patterns between the different acetogenins, with the lactone moieties positioned in the same regions as compounds 1 and 2. Therefore, in silico prediction of metabolites from bioactive ligands can contribute to the design of potent derivatives, as demonstrated in this study, which aligns with our experimental findings.