Potent Antimalarial 2-Pyrazolyl Quinolone bc 1 (Qi) Inhibitors with Improved Drug-like Properties

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 Q_i site of the Parasite bc ₁ complex, which is supported by crystallographic studies of bovine cytochrome bc ₁ complex.