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A series of 2-pyrazolyl
quinolones has been designed and synthesized in 5–7 steps to
optimize for both in vitro antimalarial potency and
various in vitro drug metabolism and pharmacokinetics
(DMPK) features. The most potent compounds display no cross-resistance
with multidrug resistant parasite strains (W2) compared to drug sensitive
strains (3D7), with IC50 (concentration of drug required
to achieve half maximal growth suppression) values in the range of
15–33 nM. Furthermore, members of the series retain moderate
activity against the atovaquone-resistant parasite isolate (TM90C2B).
The described 2-pyrazoyl series displays improved DMPK properties,
including improved aqueous solubility compared to previously reported
quinolone series and acceptable safety margin through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed
to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic
studies of bovine cytochrome bc1 complex.
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Hong, W. David; Leung, Suet C.; Amporndanai, Kangsa; Davies, Jill; Priestley, Richard S.; Nixon, Gemma L.; et al. (2018). Potent Antimalarial 2‑Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved
Drug-like Properties. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.8b00371