Planejamento, síntese e avaliação Anti-Trypanosoma cruzi de novos derivados Aminoguanidina hidrazonasa

Abstract

Chagas disease, a parasitic infection widespread in Latin America, is a serious public health problem with devastating consequences in terms of human morbidity and mortality. Existing treatment options are limited and insufficient mainly due to low efficacy and high toxicity. In order to plan new antichagasic agents, developed in this work the synthesis of five new substances containing the indole and aminoguanidine hydrazones with potential anti-T. cruzi activity and their biological evaluation. For the synthesis of scheduled substances departed from the N-phenyl-thiourea by substitution reaction with MeI, where it was converted to LQM-45 intermediate synthesized via S-alkylation reaction. This intermediate, in turn, through amination reaction with hydrazine resulted in LQM-44, which was reacted with five different indol- 3-carboxaldehydes to obtain the five new substances with potential anti-T. cruzi activity, obtained by condensation reaction. The final compounds were synthesized in yields between 62 to 99%, and characterized by 1H NMR, it was possible to observed the presence of singlets for the chemical signals of hydrogens attached to the nitrogen (NH), in a range varying between 12.63 - 7.21 ppm. Furthermore, it was also observed the characteristic signal imine (CH = N) in the range of 8.44 - 8.54 ppm. Already in the 13C NMR spectra, we observed a characteristic sign of the C = N bond in the range of 152.4 - 153.2 ppm. Mass spectrometry confirmed all synthesized substances by investigating the molecular ion peak. All substances were subjected to in vitro assessment of their anti-T. cruzi activity epimastigote in shape in addition to cytotoxicity assay in splenocytes of mice. The LQM-31 showed better activity against epimastigote form (IC50 = 10.61 μM) when compared to the other substances tested. On the other hand the substances showed CC50 ranging from 4.37 to 5.62 μM showing high cytotoxicity when compared to benznidazole. Based on the results, will be carried out further structural changes from the structure of the LQM-31, changing the ring or group linked to aminoguanidine in order to obtain new less toxic aminoguanidínicos derivatives and most active against the parasite T. cruzi.