Planejamento racional de novas cumarinas como potenciais inibidores de cisteíno proteases do Trypanosoma cruzi e Trypanosoma brucei

Abstract

Neglected diseases are responsible for causing morbidity and mortality worldwide, being prevalent in tropical and subtropical countries. Among these diseases, Chagas disease, caused by Trypanosoma cruzi, and Human African Trypanosomiasis, caused by T. brucei gambiense or T. brucei rhodesiense, constitute public health problems, mainly in countries in Latin America and sub-Saharan Africa, respectively. Pharmacological therapies currently employed in the treatment of such diseases have problems of efficacy, toxicity, and/or resistance. In this context, it is necessary to invest in the discovery of more effective drugs against these diseases. Cruzain (CRZ) from T. cruzi and a cathepsin L-like enzyme (TbrCATL) from T. brucei are cysteine proteases considered promising targets for the development of new compounds with trypanocidal activity since they play vital roles in these parasites. Coumarin analogs have been reported as promising trypanocidal agents. Therefore, this study aims to develop rationally designed coumarins aimed at inhibiting these cysteine proteases from the T. cruzi and T. brucei protozoa. Thus, to discover potential inhibitors of such targets, the fragment-based drug design (vFBDD) technique was initially applied, which made it possible to identify a coumarinthiosemicarbazone derivative (FN-27), as the most active molecule against such proteases, CRZ (IC50: 14.4 µM ± 0.02) and TbrCATL (IC50: 2.0 µM ± 0.6), in addition to exhibiting effective activity against cells infected by T. cruzi amastigotes (EC50: 5.5 µM). At the same time, a coumarin-chalcone analog (FN-10) with promising activity against T. brucei trypomastigotes (EC50: 4.8 µM ± 0.1) was also identified, but it did not demonstrate activity against CRZ or TbrCATL. Additionally, from molecular docking studies, in which FN-27 was considered a positive control, a series of 14 new coumarins was planned and synthesized for further biological evaluation. Finally, it is expected to produce potentially active molecules against the T. cruzi and T. brucei parasites, through enzymatic inhibition, as well as to help in the development of future drug prototypes.