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Lead Optimization of Second-Generation Acridones as Broad-Spectrum Antimalarials
Papireddy Kancharla1, Rozalia A Dodean2, Yuexin Li2
1Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.
Abstract:
The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. With increasing drug resistance and the absence of a clinically available vaccine, there is an urgent need for novel, affordable, and safe drugs for prevention and treatment of malaria. Previously, we described a novel antimalarial acridone chemotype that is potent against both blood-stage and liver-stage malaria parasites. Here, we describe an optimization process that has produced a second-generation acridone series with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. These findings highlight the therapeutic potential of dual-stage targeting acridones as novel drug candidates for further preclinical development.
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