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<p>Previous studies of the natural acetylenic acetogenin (2<i>S</i>,3<i>R</i>,4<i>R</i>)-3-hydroxy-4-methyl-2-(eicos-11′-yn-19′-enyl)butanolide (<b>1</b>), isolated from the plant <i>Porcelia macrocarpa</i>, indicated its <i>in vitro</i> activity against the clinically relevant form of <i>Leishmania (L.) infantum</i>, the intracellular amastigotes and no mammalian cytotoxicity. A second chemically related acetogenin, (2<i>S</i>,3<i>R</i>,4<i>R</i>)-3-hydroxy-4-methyl-2-(eicos-11′-ynyl) butanolide (<b>2</b>), 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 <b>1</b>, the 19′-oxirane-derivative (<b>3</b>) was proposed, prepared, and experimentally tested against <i>Leishmania (L.) infantum</i> amastigotes. Compound <b>3</b> presented twofold more potency than <b>1</b>, with an EC<sub>50</sub> value of 11.3 µM. Compounds <b>1–3</b> were also analyzed via molecular docking against <i>L. (L.) infantum</i> trypanothione reductase (TR) and thiol-dependent reductase 1 (TDR1), showing that the natural products <b>1</b> and <b>2</b> prefer specific regions in the active sites for lactone positioning. Docking of derivative <b>3</b> revealed interaction patterns between the different acetogenins, with the lactone moieties positioned in the same regions as compounds <b>1</b> and <b>2</b>. Therefore, <i>in silico</i> 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.</p> Graphical abstract <p></p>

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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

  • 期刊论文

  • 发表日期：

    2025年10月4日

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  • João Pedro P. Encide,
  • Ivanildo A. de Brito,
  • Maiara Amaral,
  • Andre G. Tempone,
  • João Henrique G. Lago,
  • Kathia M. Honorio

摘要

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.

Graphical abstract