American Trypanosomiasis, also known as Chagas Disease, is one of a group of neglected tropical diseases (NTDs) that plague some of the poorest people in the world. Chagas Disease infects 10 million people worldwide leading to heart and/or digestive tract damage in 30% of those infected. æ1 It is caused by the protozoan parasite Trypanosoma cruzi and is commonly transmitted through the feces of a triatomine bug. æ2 The frontline drugs benznidazole and nifurtimox are only effective against the acute stages of the disease and have adverse side effects including testicular/ovarian injuries and neurotoxicity. æ3 The acute stages of the disease often go unnoticed however with only mild flu-like symptoms mitigating the need for new therapeutics. Following up on a recent high-throughput screen led to the development of a set of imidazole based compounds that inhibit T. cruzi cytochrome P450 subfamily 51 (CYP51). A sterol 14?-demethylase, this enzyme is vital to the biosynthesis of membrane sterols for the parasite. Inhibition of CYP51 leads to a toxic buildup of C-14 methylated sterols and cell death. æ4 From this project was developed a number of imidazole-based analogs that showed better than 60-fold selectivity over host cells, including NEU-321, a potent and highly ligand-efficient inhibitor of T. cruzi CYP51.