Chagas disease is considered by the World Health Organization (WHO) one of the most important neglected tropical diseases. Endemic in Latin America, the disease is a global public health problem, affecting several countries in North America, Europe, Asia and Oceania. The disease, caused by the protozoan parasite Trypanosoma cruzi, affects around 8-10 million people worldwide. Even after a century of its discovery, the limited treatments available present low efficacy and severe side effects, highlighting the urgent need for new therapeutic options. The enzyme cruzain (EC 3.4.22.51), the major cysteine protease from T. cruzi, has been explored as an attractive molecular target in Chagas disease drug discovery. As part of our research program focused on the discovery of novel cruzain inhibitors, a series of benzimidazole derivatives was designed, synthesized and evaluated, resulting in the identification of promising lead compounds. In this presentation, we describe the discovery and subsequent optimization of benzimidazoles to afford a number of novel reversible competitive and non-competitive inhibitors with low nanomolar potency and encouragning anti-T. cruzi properties.

Structure-activity relationships for a series of benzimidazole derivatives as cruzain inhibitors

251st National Meeting (2016)

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