PROJECT SUMMARY New drugs to treat malaria, ideally with unique chemical structures and mechanisms of action, are urgently needed. Optimal drug candidates for the treatment and prevention of malaria will have potent activity against cultured parasites and in animal models of malaria, be rapidly active against erythrocytic malaria parasites, be orally bioavailable, have extended pharmacological exposure, and be safe for administration to humans. This application builds on prior studies by our group that identified benzoxaboroles as promising antimalarials and a Phase I SBIR project between Reactive Biosciences and UCSF that identified two new series of boron- containing compounds with potent antimalarial activity. Phase II of this program will allow us to execute a thorough lead optimization program designed to deliver a candidate antimalarial compound that is potent, orally bioavailable, and safe for use. Accordingly, our specific aims will be to: 1) optimize the antimalarial activity and drug-like properties of lead boron-containing compounds, 2) characterize mechanisms of action and resistance to drive lead optimization, 3) characterize the pharmacokinetic profiles, in vivo antimalarial efficacy, and safety of optimized boron-containing antimalarials, and 4) advance an optimized boron-containing compound to Candidate status.