ESTUDO QUÍMICO DOS FRUTOS E XILOPÓDIO DE AIOUEA TRINERVIS – AVALIAÇÃO BIOLÓGICA E IN SILICO FRENTE A TRYPANOSOMA CRUZI

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, is considered a global public health problem, with an estimated 6 to 7 million people infected worldwide. Synthetic drugs traditionally used for treatment have limited efficacy, in addition to causing systemic toxicity, thus leading to the investigation of plant secondary metabolites as a promising alternative source of trypanosomicidal agents. In a previous study carried out by our research group, the ethanolic extract of the xylopodium of Aiouea trinervis revealed the presence of butanolides with anti-T.cruzi activity. In silico studies make it possible to evaluate the biological potential of a large number of compounds in a short period of time, highlighting molecular docking. Therefore, the present work aimed at evaluating the biological and in silico potential against T.cruzi of the fruits, domes and xylopodium of A. trinervis. To this end, the fruits, domes and xylopodium were extracted with 95% EtOH. The ethanolic extract of the fruits and the xylopodium, separately, were subsequently partitioned between MeOH/H2O 9:1 and hexane; MeOH/H2O 1:1 and CH2Cl2; and MeOH/H2O 1:1 and AcOEt, while the ethanolic extract of the domes was re-extracted using CH2Cl2. The hexane and CH2Cl2 phases of the fruits and the CH2Cl2 extract of the domes were subjected to different chromatographic processes, such as adsorption, exclusion and high-performance liquid chromatography, aiming to isolate and purify the compounds. The hexane phase of the xylopodium underwent different chromatographic processes focused on obtaining isoobtusilactone A; The structures of these compounds were established based on analysis of 1H NMR and 13C HPLC-DAD-MS/MS data. The extracts, phases and isolated compounds were tested against epimastigote forms of T.cruzi. The enzymes glycosomal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cruzin were used for molecular docking studies. The structure of obtusilactone A was used as a basis for molecular modeling. The pharmacokinetic parameters of promising compounds were evaluated. As a result, the chemical study of the fruits, domes and xylopodium led to the isolation of ten substances, being a sulfonated amide, ((E)-3-(methylsulfinyl)-N-phenethylacrylamide), a lignan, sesamin, three butanolides (( S,E)-4-hydroxy-5-methylene-3-tridecylidenedihydrofuran-2(3H)-one, (R,E)-4-hydroxy-5-methylene-3-pentadecylidenedihydrofuran-2(3H)-one and ( R,E)-4-hydroxy-5-methylene-3-heptadecylidenedihydrofuran-2(3H)-one), a secobutanolide (secosubamolide), three flavonoids, ((+)-catechin, (-)-epicatechin and taxifolin) and acetyl tributyl citrate, in addition to a mixture of triglycerides. From semi-synthesis, the compound acetylsecosubamolide was obtained. The three butanolides, the sulfonated amide and acetylsecosubamolide are unpublished in the literature. Regarding the biological potential, the extract, the hexane and CH2Cl2 phases of the fruits, the three butanolides and the sulfonated amide showed activity against the epimastigote forms of T.cruzi. Molecular modeling of isoobtusilactone A led to three theoretical butanolides that are potentially active against the enzymes tested. The isolated and theoretical butanolides together with the sulfonated amide showed favorable pharmacokinetic parameters. Given the results found, the fruits of A.trinervis showed biological potential against the epimastigote forms of T.cruzi. The results of in silico studies, combined with in vitro studies, highlighted the potential of the butanolide class as anti-T-cruzi agents.