1 research outputs found
Discovery, Synthesis, and Optimization of Antimalarial 4(1<i>H</i>)‑Quinolone-3-Diarylethers
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 4Â(1<i>H</i>)-quinolone-3-diarylethers. The initial prototype, ELQ-233,
exhibited low nanomolar IC<sub>50</sub> 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