Complexos de rênio e tecnécio com derivados do Megazol: potenciais agentes multifuncionais para o tratamento e diagnóstico da doença de Chagas

Abstract

Chagas disease (CD) is a neglected disease that affects mainly Latin American People. The treatment and diagnosis, particularly during the chronic phase, are ineffective due to the lack of symptoms and low parasitemia. For this reason, CD requires not only new trypanocidal agents but also more efficient diagnostic techniques. For improving such problems, new rhenium complexes (natural isotope) can be employed in Chagas chemotherapy, while analogous 99mTc complexes can be used to diagnose/monitor the disease while the combination of them can lead to the development of a theranostic device (therapy + diagnosis). Therefore, the main objective of the present work was the synthesis, characterization and evaluation of the trypanocidal activity of complexes containing the fac-{185/187Re(CO)3} fragment with derivatives from the trypanocidal drug known as Megazol. The peripheral structure of Megazol (LH,H) was modified to obtain the compounds LR,R (R = H, Me and R= Me, Me), which were used in the syntheses of complexes of composition [ReBr(CO)3LR1,R2]. The techniques employed in the structural determination and study the chemical properties of compounds were: elemental analysis, absorption spectroscopies in the IR and UV-vis region, NMR (1H and 13C), HR-ESI-MS, HPLC/UPLC, single-crystal XRD and DFT methods. The trypanocidal activity of the compounds was evaluated in vitro against the intracellular form of T. cruzi. The results showed that the ligand complexation to the {Re(CO)3}+ core does not significantly change the trypanocidal activity and, with exception of the [ReBr(CO)3LMe,Me] complex, all compounds exhibited SI better than the standard drug, benznidazol (Bz). In addition, the interaction of megazol and its Re complex was evaluated, by both experimental and computational methods, with T. cruzi Old Yellow Enzyme (TcOYE) protein. The data showed that megazol as well as the metallic complex presented higher affinity for TcOYE than Bz. Finally, it was possible to affirm that the labelling of megazol with 99mTc was carried out successfully, although the results have indicated the Re complexes, used as standard, were not homologous with the 99mTc complexes, probably, due to a charge difference between them. Nevertheless, the combination of the Re and 99mTc compounds studied here represents an important step towards the development of a theranostic device for CD.