Planejamento, síntese e estudo da relação entre estrutura química e atividade biológica de uma classe de sulfonilpiperazinas potente contra o Trypanosoma cruzi.

Abstract

Chagas disease, caused by the parasite Trypanosoma cruzi, is considered by the World Health Organization (WHO) as a neglected tropical disease. It is endemic in 21 countries in Latin America and infects about six to seven million people worldwide per year and until this day, its cure has not been found. The medicine most used for Chagas disease treatment is benznidazole. However, it only presents moderate efficacy in the disease’s initial phase; in addition, it is not accessible to most of the infected people and causes a series of side effects that leads patients to abandon treatment. Within this context, it is necessary to develop new drugs that are more efficient, less toxic, and low cost for Chagas disease treatment. In this work, three sulfonamides derivatives hits (1-3) were selected from Pena’s and collaborators work, 2015, which stand out for their potent biological activity against T. cruzi (IC50 < 1 M) and low cytotoxicity in HepG2 human non infected cells (IC50 > 50M). This work presents the synthesis of hit 2, the synthesis attempt of hit 1 and also the planning, synthesis and anti-T.cruzi evaluation of the analogous compounds of hits 1-3 named in this woek as a class of sulfonylpiperazines. There were 28 synthesized compounds which were sent to in vitro incial trials against T. cruzi, 26 being unpublished. With these results, it was possible to establish a preliminary structure activity relationship of this sufonylpiperazine series. The hit 2 showed IC50 19 mM e CC50 227 mM and compounds 44b (IC50 3,0 mM, CC50 463 mM e IS 156) and 52a (IC50 3,0 mM, CC50 327 mM e IS 107) showed high anti-T.cruzi activity and low toxicity in mouse L929 cells. Although 44b and 52a are less selective, they presented equipotency with benznidazole (IC50 3,8 mM, CC50 2401 mM e IS 625), used as the control in the in vitro assay. Therefore, this work contributes with the development of new drug candidates that are more effective, less toxic and of low cost for the treatment of Chagas disease.