Second-Generation Novel Liver Stage Active Antimalarials

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PROJECT SUMMARY/ABSTRACT The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. We have developed a novel antimalarial acridone chemotype with dual stage efficacy against both liver stage and blood stage malaria, as well as single-dose cure ability and potential to prevent relapsing infection. The ability to combat multiple stages of the infection represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as the malaria eradication effort proceeds. A rigorous optimization process has produced a series of second-generation acridones with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. Our overarching goal is to develop a novel antimalarial that is safe in individuals with G6PD deficiency, and in the most vulnerable populations – pregnant women and children, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce second-generation candidates for full preclinical evaluation that retain the broad-spectrum features and demonstrate enhanced efficacy, safety, solubility, and metabolic/pharmacokinetic profiles; to investigate the propensity for drug resistance to selected acridone candidates and identify the molecular target(s) through whole genome sequencing and analysis; and to explore mode(s) of action for these liver stage active antimalarial acridones using functional assays and bioanalytical approaches.