MOLECULAR CHARACTERIZATION AND EVALUATION OF THE ANTIPARSITARY POTENTIAL OF ACETYLENIC ACETOGENINS ISOLATED FROM THE SEEDS OF Porcelia macrocarpa (WARM.) R. E. FRIES (ANNONACEAE)
Plants have been highlighted as important sources of molecules to be explored for the development of prototypes and potential drugs for the treatment of the most diverse diseases, especially those considered neglected. In this context, in view of Chagas' disease, whose etiological agent is the protozoan Trypanosoma cruzi, which affects more than six million individuals, and whose effective therapeutic arsenal available for treatment is still very small and unsatisfactory. In Brazil, benznidazole is the only drug available, which is very limited due to side effects. Thus, the search for new prototypes, mainly those based on structures of natural products, is fundamental. In this aspect, the present work aimed to carry out the phytochemical study of Porcelia macrocarpa (Warm.) R. E. Fries (Annonaceae) seeds to obtain metabolites with anti-T. crossed. In an initial prospective study, it was observed that the CH2Cl2 extract of the seeds showed significant activity for the trypomastigote forms of T. cruzi (100% kill at 200 μg/mL). The 1H and 13C NMR analysis of the extract in CH2Cl2 showed that it is mainly constituted by acetylenic acetogenins. Thus, this material was subjected to chromatographic fractionation, obtaining eight structurally related acetylenic acetogenins (1 - 8), including six compounds unpublished in the literature, (2S,3R,4R)-3-hydroxy-4-methyl-2-(n- octadec-11′-in-17′-enyl)butanolide (1), (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-docos-11′-in-21′-enyl) butanolide (3), (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-tetracos-11′-in-23′-enyl)butanolide (4), (2S,3R,4R) -3-hydroxy-4-methyl-2-(n-octadec-11′-ynyl)butanolide (5), (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-docos-11 ′-ynyl)butanolide (7) and (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-tetracos-11′-ynyl)butanolide (8), whose structures were determined by NMR analysis is at. The antiparasitic activity of compounds 1 – 8 showed EC50 values for trypomastigote (extracellular) forms of 1.9; 6.7; 16.7; 44.1; >150; 9.4; 8.4 and 5.6 µM, respectively, and reduced cytotoxicity against NCTC cells at the maximum concentration tested (CC50 > 200 µM). In relation to the amastigote forms (intracellular) compounds 1, 2, 3, 6, 7 and 8 showed EC50 values of 7.6; 10.9;13.9; 9.2; 9.2 and 1.1 µM respectively. Among the acetogenins, it is worth noting that compound 8 showed high selectivity (IS > 181.8) for the amastigote forms of T. cruzi. These results suggest that side chain extension plays an important role in the activity. The results obtained so far contribute to the chemosystematics of the P. macrocarpa species, as it describes for the first time the occurrence of compounds 1, 3, 4, 5, 7 and 8 in the literature. Furthermore, it was possible to observe that the antiparasitic potential presented by the compounds are promising for the development of prototypes to obtain new drugs for the treatment of Chagas disease.