New drugs for malaria are greatly needed. This program is directed toward the development of new boron-containing small molecules as antimalarial drugs. Our preliminary results suggest that novel boron-containing small molecules (oxaboroles) have potent antimalarial activity and, importantly, are likely to meet standard pharmacokinetic and safety criteria for new drugs and also the unique requirements for antimalarials. We hypothesize that a systematic drug discovery program will identify optimized oxaboroles that are relatively simple to produce and meet established criteria for new antimalarial agents. We further hypothesize that a systematic approach will identify a specific antimalarial mechanism of action for oxaboroles. Appreciation of the mechanism of action will aid in drug optimization and in the understanding of potential drug resistance. Our program will entail continued collaboration between Anacor, the world leader in boron chemistry and a malaria research group at the University of California, San Francisco with nearly two decades experience in antimalarial drug discovery. Specific aims of our program will be 1) hit-to-lead discovery of oxaborole antimalarials, 2) lead optimization of oxaborole antimalarials, and 3) characterization of the mechanism of action and resistance for lead oxaboroles. We anticipate that, within the time-frame of this project, we will identify a candidate oxaborole antimalarial for development and also back-up lead compounds, and that we will gain important insights into the antimalarial mechanisms of action of these compounds