Discovery, synthesis, and optimization of antimalarial 4(1H)-quinolone-3-diarylethers

Aaron Nilsen, Galen P Miley, Isaac P Forquer, Michael W Mather, Kasiram Katneni, Yuexin Li, Sovitj Pou, April M Pershing, Allison M Stickles, Eileen Ryan, Jane Xu Kelly, J Stone Doggett, Karen Louise White, David J Hinrichs, Rolf W Winter, Susan Ann Charman, Lev N Zakharov, Ian C Bathurst, Jeremy Burrows, Akhil B VaidyaMichael K Riscoe

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73 Citations (Scopus)


The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.
Original languageEnglish
Pages (from-to)3818 - 3834
Number of pages17
JournalJournal of Medicinal Chemistry
Issue number9
Publication statusPublished - 2014

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