Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.

Abstract

Chagas disease is treated only by two drugs, nifurtimox (1) and benznidazole (2). However, in addition to these drugs not being effective in all stages of infection, they have severe side effects, which justifies the search for new alternatives for the treatment of this serious disease. Literature data describe the interference of non-steroidal anti-inflammatory drugs on Trypanosoma cruzi trypomastigote infection process on mammalian cells. The mechanism of action of these drugs occurs on the isoforms of the enzyme cyclooxygenase, important for the establishment of parasite infection. Additionally, the toxic effects of nitroaromatic compounds are well known, and T. cruzi is greatly affected by the action of these molecules in its redox equilibrium. With this information, we proposed in this work the investigation of the trypanocidal activity of the nimesulide (3), non-steroidal antiinflammatory drug, which has in its structure the nitro-aromatic toxicophoric group. The drug repositioning approach, as presented here aiming at the possible trypanocidal activity of nimesulide (3), is an important resource in the discovery of drugs applicable to the treatment of neglected diseases. Another strategy, developed in parallel, involved the use of molecular hybridization in the preparation of two nimesulide derivatives (3) withing the structure of natural amide piperine. The results obtained from the biological evaluations carried out indicated antiparasitic activity of nimesulide (3) on the different evolutionary forms of the parasite. In addition, of the two molecular hybrids constructed, the hybrid H1, in which the aromatic nitro portion was preserved, presented trypanocidal action, while the hybrid H2 significantly lost activity with the removal of the nitro group from its structure. This set of results allowed us to point to the nitro portion present both in the structures of nimesulide (3) and its hybrid H1 as pharmacophoric group for the trypanocidal activity validating the hypothesis of this study. The results obtained in the evaluation of ultrastructural changes in T. cruzi epimastigotes treated with nimesulide show the disorganization of the mitochondrial structure, corroborating the possible interference of the drug on the redox equilibrium of the parasite.