Potent Antimalarial 2-Pyrazolyl Quinolone <i>bc</i> ₁ (Q_i) Inhibitors with Improved Drug-like Properties.

ABSTRACT: 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 t

SUBMITTER: David Hong W 

PROVIDER: S-EPMC6295854 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature