Desenvolvimento de tyriazóis derivados da piperina inibidores da CYP51 de Trypanosoma cruzi: otimização de um modelo de previsão de atividade teórica, síntese e atividade in vitro

Abstract

Chagas disease (CD) is a neglected tropical disease caused by the parasite Trypanosoma cruzi and presents millions of cases in several countries. Currently there are no vaccines for CD prevention and there are only two drugs for its treatment, but in Brazil, only benzonidazole is used and is ineffective on disease’s chronic phase. Thus, research for new drugs becomes essential. The enzyme sterol 14α-desmethylase (CYP51) belongs to the ergosterol biosynthesis pathway, which are fundamental for the integrity of the T. cruzi’s cell membrane. Its inhibition causes the parasite’s death and it can be promoted by the coordination of heterocyclic compounds with the iron atom of the enzyme’s heme group. On a previous work, a theoretical model of activity prediction for new inhibitors of CYP51 (T. cruzi), based on experimental and theoretical parameters calculated by molecular modeling, which was used for design new triazole piperine derivatives. On this current work, the original theoretical model was optimized using the semi-empirical PM7 method instead of PM6 and a selectivity study was done by molecular docking of heterocyclic compounds in T. cruzi’s CYP51 and H. sapiens’s CYP51. The most promising compounds, planned by the original model, were synthesized, evaluated in vitro against T. cruzi and they were tested for CYP51 inhibition. The new model presented a multiple correlation coefficient slightly higher than the original. The docking study indicates a likely selectivity of the compounds for the parasite’s enzyme. The compounds showed activities against trypomastigote forms, in agreement with the general predictions made by the model, and low cytotoxicity in primate cells. Preliminary enzyme inhibition assays indicated that the compounds designed with the model are in fact capable of inhibiting the parasite's CYP51.