Avaliação de híbridos de metronidazol no tratamento da doença de Chagas experimental

Abstract

Chagas' disease has as one of its main challenges the development of a drug that may be effective in all stages of the disease and with low toxicity since the current ones do not meet these needs. One of the drug design strategies is molecular hybridization, which enables the reduction of side effects and improve affinity and efficacy with concerning to isolated compounds. Thus, the objective of this work was to evaluate the anti-T. cruzi efficacy of new hybrid metronidazole compounds coupled with eugenol derivatives with in vitro and in vivo tests. Previous worked tested in vitro the anti-T. cruzi efficacy and the toxicity of 21 compounds evaluated Against both epimastigote and trypomastigote forms of the parasite to mesuare the efficacy (definition of IC 50 ) and toxicity of the compounds (CC 50 ). The three compounds with the best results in the in vitro experiment (CEI02, CEF05, and MG02) were tested in an in vivo screening experiment to define the compound with the best activity, lowest toxicity, and the most optimized dosage of the same, in an experiment of longer duration and combination therapy with Bz, in addition, CEF05 was tested against amastigote forms. In this final experiment, biological, immunological, and histological parameters of therapeutic efficacy were evaluated. The results obtained from the in vitro tests demonstrate that all compounds showed trypanocidal activity against the parasite and presented a satisfactory degree of toxicity, with MG02 being the most satisfactory compound. In vivo screening showed that the best result in reducing parasitemia was the hybrid CEF05 at dosages of 50 and 100mg/kg, which was the only one to prevent the death of all animals and with less weight loss. It was possible to observe, from the results of the in vitro experiment against amastigote forms, that the hybrid presented superior results to benznidazole. From the results of the “definitive” in vivo experiment, CEF05 monotherapy did not eliminate T. cruzi from the hosts, but it reduced the parasitemia, avoided mortality, reduced the animals' weight loss, and reduced the heart inflammatory infiltrates and the production of pro- inflammatory cytokines. In addition, the potentiating of trypanicidal effect of Bz, verified through parasitemia. With the results obtained, it is possible to conclude that although the highest activity in the in vitro tests was observed with the use of MG02, better results were observed in vivo with the use of the hybrid CEF05, which stood out for its greater activity against T. cruzi and reduction of toxic effects.