Planejamento de potenciais inibidores de enzimas do parasito Trypanosoma cruzi: síntese, docking e avaliação biológica

Abstract

Neglected diseases constitute a major public health problem worldwide, quantifying a total of 1 billion people suffering from some kind of infection of bacterial, viral or parasitic origin. Among them, we can highlight Chagas disease, caused by the parasite Trypanosoma cruzi, which affects more than 8 million people around the world. In order to discover new active compounds against T. cruzi, developed herein the synthesis of new prototypes of thiophene-2- thioureic and 2-iminothiazolidine rationally designed with potential antichagasic activity, biological evaluation and study docking. Initially, the start material was the polysubstituted thiophene derivatives synthesized via Gewald reaction, which were converted into thioureic derivatives and then cyclized with five different electrophiles, generating thiophene-2- iminothiazolidine derivatives. The intermediates and final compounds were synthesized in yields between 40 and 98%, and characterized by NMR. For docking study was initially performed by minimizing the energy of the ligands by ArgusLab® software, using AM1, and applying the software AutoDock Tools® and AutoDock Vina®, using the Gasteiger method. All compounds were evaluated in the anti-T. cruzi assays, in vitro, and the most active serie was selected for the cytotoxicity assay (MTT) in J774 cell line. It was possible to determine the enzymes involved in the probable mechanisms of action for the ligands. It has been observed that in 50% of cases, TcDHFR enzyme is the main target of the new compounds, in amastigotes. The pharmacological tests in amastigotes and trypomastigotes, line of C2C12 and MK2 cells was established as validation for the theoretical studies. The compound 3d probably develops its mechanism of action by inhibition of the enzyme TcTS (IC50= 10.3 µM) in trypomastigotes of the parasite. Since the compound 7c possibly acts by inhibition of the enzyme TcDHFR (IC50= 9.2 µM) in amastigotes. In additional, it was proposed that the compound 7b carries out its activity by inhibition of the enzyme TcDHFR (IC50 = 5.0 µM). Finally, it was observed that the most active compounds obtained in this study were more effective than the benznidazole, gold standard drug used in pharmacotherapy clinical of the Chagas disease, additionally has a low cytotoxicity (CC50> 100 µM).