Síntese de derivados N-fenetilcarboxamidas e avaliação da atividade anti-Trypanosoma cruzi

Abstract

Chagas disease, caused by the protozoan T. cruzi, is endemic in 21 Latin American countries and it’s classified by the World Health Organization as one of the 20 neglected tropical diseases. The chemotherapy is based on the use of benznidazole and nifurtimox, old drugs that show low efficacy in the chronic phase, in addition to presenting several side effects and long treatment periods. Aiming to obtain compounds with potential anti–T. cruzi activity, our research group has synthesized several pyrazole derivatives and evaluated them against the infective forms of the protozoan. Continuing the group’s research projects, the objective of this work is to synthesize and assay the trypanocidal activity of 20 1-aryl-N-phenethyl-1H-pyrazole-4-carboxamide derivatives 1(a–t) and three N-phenethyl-heteroaryl-acetamide derivatives 6(a′–c′). The final products 1(a–t) and 6(a′–c′) were synthesized with yields ranging from 15–93%, and 32–47%, respectively. The synthetic route used for achieving compounds 1(a–t) consists of four steps, synthetizing a total of 60 key intermediates. The 6(a′–c′) derivatives were obtained from heteroaryl-acetic acid derivatives. All the 23 final compounds, 1(a–t) and 6(a′–c′), were characterized by Fourier-Transform Infrared Spectroscopy, Nuclear Magnetic Resonance of 1H and 13C, and High-Resolution Mass Spectrometry. The final compounds are being evaluated against the amastigote (intracellular) and trypomastigote (extracellular) forms of the T. cruzi, besides cytotoxicity on Vero cells. Until now, biological activity results of 17 compounds of the 1(a–t) series were obtained. None of them showed cytotoxicity effect (CC50 > 300 M) and were ineffective against the trypomastigote form (IC50 > 100 M). However, the derivative 1-(2,4-dichlorophenyl)-N-phenethyl-1H-pyrazole-4-carboxamide 1d yielded the best result against the amastigote form, whose IC50 value was 31.68 ± 5.16 M and the selectivity index of 15.78.