Síntese de inibidores potenciais da tripanotiona redutase: base para o desenvolvimento de novos fármacos para tratamento da doença de Chagas e Leishmaniose

Abstract

Trypanothione reductase (TR) is an enzyme found in trypanosomatids, which is involved in the reduction of trypanothione disulfide T[S]2 to the dithiol T[SH] and represents a key enzyme for the parasite antioxidant defense. Despite the similarity of the TR-T[S]2 system with its analogue glutathione-glutathione reductase (GR), there are significant differences in the active sites of these two enzymes that can be exploited in the development of selective inhibitors. In the present work, a series of the bis-(arylmethylidene) cycloalkanones was designed as potential inhibitors of TR, taking the 2,5-bis(4-aminomethylphenyl)furan as lead compound. The compounds were synthesized by aldol condensation of cycloalkanones with a variety of aldehydes, in order to establish the relationship between structure and activity. The selectivity of the compounds was tested by determining their inhibitory activity against TR and GR. The activity of the compounds was evaluated against amastigotes forms of Trypanosoma cruzi and promastigotes forms of Leishmania amazonensis. The cytotoxicity of the compounds to non-infected fibroblasts was also determined. Five compounds displayed activity against T. cruzi and six showed leishmanicidal activity. The diamine 13 exhibited significant anti-leishmanial activity (IC50 13.7 µM), low cytotoxicity (IC50 > 83.7 µM) and was also able to inhibit the TR activity (IC50 40.4 µM). Besides compound 13, two compounds (1b and 5b) showed a good correlation between enzyme inhibition and anti-leishmanial activity. However, these compounds were cytotoxic to mouse fibroblast L929 cell line. Only the diazide derivative 12 was able to inhibit GR activity by about 50%, suggesting considerable selectivity for this class of compounds. Furthermore, docking studies were performed to investigate the mode of interaction of the ligands to the TR. Among the synthesized compounds, 13 and 7a can be considered as lead candidates for the further development of new antiprotozoal agents against leishmaniasis and Chagas' disease, respectively.