Navegando por Palavras-chave "Acetogenina"

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    Porcelia macrocarpa r. E. Fries (annonaceae): prospecção de novos compostos com potencial atividade antiparasitária
    (Universidade Federal de São Paulo (UNIFESP), 2019-04-26) Oliveira, Emerson Alves De [UNIFESP]; Lago, João Henrique Ghilardi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Despite the devastating scenario imposed by neglected tropical diseases (NTDs) that affect more than 1.4 billion people worldwide, especially in developing countries, there are no public and private investments for the diagnosis, treatment and research of new therapies. Many of these NTDs are treated with very old, low efficacy drugs that have severe side effects and high toxicity. Brazil has 3 million chronically ill patients suffering from Chagas' disease (CD), an NTD whose etiologic agent is Trypanosoma cruzi. Treatment of CD in the country is performed with a single drug, benznidazole that is ineffective against all stages of the disease. In this context, the present study performed the biomonitoring phytochemical analysis by antiparasitic assays of hexane and dichloromethane extracts of P. macrocarpa seeds, which allowed the isolation of four acetylenic acetogenins (A) (2S, 3R , 4R)-3-hydroxy-4- methyl-2-(n-eicos-11'-in-inyl)butanolide, (B) (2S,3R,4R)-3-hydroxy-4-methyl-2-(neicos- 11'-in-19'-enyl)butanolide, (C) (4R)-3-hydroxy-4-methyl-2-(n-eicos-11'-in-19'- enyl)but-2-enolide (D) 3-hydroxy-4-methylene-2-(n-eicos-11'-in-19'-enyl)but-2- enolide, two of which have not been published in the literature (C and D). All of acetogenins isolates were subjected to antiparasitic testes and two (C and D) were more potent than the standard drug against the amastigotes and trypomastigotes forms of T. cruzi, with IC50 values of 3.6 μM and 27.7 μM (amastigote/trypomastigote) for C and 0.4 μM and 23.0 μM (amastigote/trypomastigote) for D. In addition, all active acetogenins (B-D) were evaluated against NCTC cells, which had no cytotoxicity at the highest concentration (200 μM), except for D, where CC50 was 80.0 μM. The mechanism of action of the most potent acetogenins (C and D) was investigated and the results suggested that the plasma membrane depolarization and the observed change in the electrical potential of the mitochondrial membrane of the parasite may be a result of the lethal action of C and D. Complementary in silico ADMET studies were perfomed with active acetogenins B-D and the following features were indicated: (i) all were suitable for human intestinal absorption (HIA+), (ii) none were substrates of CYP2D6, (vi) except for D, none were substrates for CYP2C9, and (vii) none acted as inhibitors of the following isoforms: CYP3A4, CYP2C9, CYP2C1I9, CYP2D6, or CYP1A2. In addition the active acetogenins B-D are not mutagenic (Ames), carcinogenic, prone to colloidal aggregation. They are also not hERG K+ channel blockers (multi-class) no pan-assay interference compounds (PAINS). Thus, acetogenins C and D can be considered excellent prototypes for the development of drugs, aiming at the effective treatment of Chagas' disease in the acute and chronic phases of the disease.