Novel Multiple-Stage Active Antimalarials

PROJECT SUMMARY/ABSTRACT Malaria has been a deadly enemy of mankind throughout history, currently affecting over 200 million people annually along with approximately half a million deaths. Full or partial drug resistance to current therapies, specifically quinolines, antifolates, artemisinin derivatives, and other artemisinin partner drugs, is of great concern. The newly approved and implemented vaccine does not offer complete sterilizing immunity, hence there is still an urgent need to strengthen the antimalarial drug pipeline through the discovery and development of novel, affordable, effective, and well-tolerated multiple-stage active antimalarials that operate by new mechanisms. This proposal is based upon an established collaboration between the Kancharla, Kelly, Roth and Fidock laboratories focusing on the natural products inspired novel tambjamine antimalarials. A rigorous optimization strategy has produced several multiple-stage active lead tambjamine candidates that exhibited superior curative oral efficacy in different animal models while exhibiting good safety and metabolic profiles. The objective of the current research proposal is to advance early leads identified in the previous funding period into late-stage lead candidates with potential for future advancement to clinical trials. The principal goals will be improving the pharmaceutical properties of the current leads, increasing in vivo efficacy, oral bioavailability, and metabolic stability in murine models while decreasing toxicity, and investigating mode(s) of action for the novel TA chemotype. Overall, the long-term objective of the proposed research is to develop a novel, affordable, metabolically stable, orally bioavailable, effective and well-tolerated drug with broad- spectrum activity against multiple-stages of malaria infection, which ultimately can be co-formulated with other antimalarials in a synergistic combination to prevent and treat malaria, including radical cure in patients with G6PD deficiency, thus supporting world-wide elimination of the disease.