ACS Omega 2025 May 03;1021:21747-21754. doi: 10.1021/acsomega.5c01382.

Anti-Trypanosoma cruzi Effect of Fatty Acids from Porcelia macrocarpa Is Related to Interactions of Cell Membranes at Different Microdomains as Assessed Using Langmuir Monolayers.

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Chagas disease, a parasitic disease caused by the protozoan Trypanosoma cruzi, is an important health problem affecting more than 8 million people worldwide. The only available treatments, benznidazole and nifurtimox, display high toxicity and reduced efficacy in the chronic phase of the disease. To find new natural products with anti-T. cruzi activity, the CH2Cl2 extract of Porcelia macrocarpa R. E. Fries (Annonaceae) seeds was subjected to bioactivity-guided fractionation. Through several chromatographic steps, one group consisting of a mixture of 10 chemically related fatty acids (1-10) was obtained. This group showed activity against trypomastigote forms with an EC50 of 4.0 μg/mL, similar to the standard drug benznidazole (EC50 = 3.9 μg/mL). It also showed activity against the intracellular amastigotes, with an EC50 of 0.5 μg/mL, close to the efficacy of benznidazole (EC50 = 0.9 μg/mL). In addition, the mixture of 1-10 showed no toxicity against murine fibroblasts (CC50 > 200 μg/mL), resulting in SI > 49 and >416 in trypomastigotes and amastigotes, respectively. The interaction of the mixture with the protozoan membrane models was also assessed with Langmuir monolayers composed of three phosphatidylethanolamine (PE) lipids with different degrees of acyl chain unsaturation and in the presence of mucins. Compounds 1-10 favorably interact with all tested lipids, with maximum insertion pressure (MIP) values above 40 mN/m and positive synergy values, suggesting penetration through the mucins. Furthermore, the mixture has a higher affinity for monounsaturated lipids bound to mucins, with an MIP value of 57.59 ± 2.59 mN/m. Based on these results, the effect of compounds 1-10 against T. cruzi can be related to interactions with the parasite cell membranes.

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