444 DEVELOPMENT OF NEW DRUGS FOR CHAGAS DISEASE

Chagas disease results from infection with the protozoan pathogen Trypanosoma cruzi (T. cruzi). The disease is endemic in South and Central America with > 16 million people chronically infected and ≈14,000 deaths per year. Current treatment options are inadequate to cure this infection; thus, research is needed to discover better chemotherapeutics. We have an ongoing project making inhibitors to a key enzyme involved in sterol biosynthesis of T. cruzi, sterol 14-demethylase (Tc14DM). This enzyme, the target of azole antifungal drugs, is a well established antimicrobial target. We hypothesize that new compounds can be synthesized with optimal anti-T. cruzi activity, and these will be sufficiently active to cure animals (and humans) with chronic T. cruzi infection. We have discovered two new chemical classes that bind the Tc14DM and that have potent activity against T. cruzi cultures with ED50 values in the 1-10 nM range. The active compounds are a series of disubstituted imidazoles and another series derived from the cancer drug tipifarnib. We have shown the disubstituted imidazoles dramatically suppress T. cruzi parasitemia in the mouse model of Chagas disease. Working in collaboration with chemists at Yale University and University of Washington, we are working to optimize these lead compounds for pharmacological properties and efficacy against T. cruzi.