[摘要]:Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an existing clin. compd. with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clin. trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14a-demethylase (14DM). We rationally developed tipifarnib analogs that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compd. has picomolar activity against cultured T. Cruzi and is efficacious in a mouse model of acute Chagas disease.