Project Summary Neglected and emerging tropical diseases caused by eukaryotic pathogens impact hundreds of millions of the world's population. These diseases are largely endemic to Asia, the Middle East, Africa, South and Central America, yet they pose a significant threat to global public health, including that of the United States. Hence, continued effort to control, eliminate, and provide safe and effective treatment options is crucial. In this SC3 project, our efforts will be devoted to the optimization, identification, and validation of new chemical entities as potential pre-clinical drug candidates for malaria, caused by Plasmodium falciparum, and Human African trypanosomiasis (HAT), caused by T. brucei gambiense/rhodesiense. We have identified a series of chemical entities that will serve as templates for further discovery and development. In this project, we will employ a combination of structure-, and natural products–based drug discovery approaches. In addition, we will structurally characterize the molecular interactions between the cysteine protease-drug target from T. brucei and its inhibitors. The successful execution of the aims and objectives for this project will add to the knowledge of structural chemotypes important for antitrypanosomal and antimalarial drug discovery, and it will add to the drug development pipeline for HAT and Leishmaniasis.