Benzoxaborole-based antimalarial drug discovery

Modified Project Summary/Abstract Section New drugs to treat malaria, ideally with unique chemical structures and mechanisms of action, are urgently needed. Optimal antimalarials will be orally bioavailable, have extended pharmacological exposure, be safe for administration to children and pregnant women, be rapidly active against erythrocytic malaria parasites, and ideally also be active against other life cycle stages of malaria parasites. This application builds on a recent collaboration between Anacor and UCSF that established benzoxaboroles as promising new antimalarial agents. Recently, a new collaboration has developed including the original team at UCSF and former Anacor collaborators now at Boragen. We hypothesize that the proposed novel benzoxaboroles will exert potent antimalarial activity and fulfill necessary criteria to enable progression to antimalarial drug development. This Phase I SBIR application concerns the study of new classes of benzoxaboroles to establish scaffolds for detailed discovery and development in a Phase II program. Our specific aims will be: 1) to characterize structure activity relationships for antimalarial activity of benzoxaboroles, 2) to characterize the drug-like properties of benzoxaboroles with antimalarial activity, and 3) to characterize ex vivo and in vivo activity, drug interactions, and initial pharmokinetic data for advanced hits selected based on results from Aim 1 and Aim 2 studies. We anticipate that our studies will lead to the identification of multiple compounds with promising in vitro activity (Aim 1) and favorable drug-like properties (Aim 2), laying the groundwork for advancement to additional in vitro and in vivo studies in Aim 3, and then to more substantial characterization of leads in Phase II of the SBIR program.Modified Public Health Relevance Section Malaria, especially falciparum malaria in Africa, remains one of the greatest infectious disease problems in the world, with an estimated 228 million cases and 405,000 deaths from malaria in 2018.[1,2] Despite important advances, for much of the tropics malaria remains an overwhelming burden.[2] With no highly effective vaccine available, and limited effectiveness of vector control measures,[3] our most important tools for malaria control, including both the treatment of symptomatic infection and the prevention of malaria in endemic populations and travelers, are effective antimalarial drugs, in particular artemisinin-based combination therapies (ACTs).[4]