Potent Antimalarial 2-Pyrazolyl Quinolone bc 1 (Q i ) 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 antimalarial potency and various 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 IC (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 cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q site of the parasite complex, which is supported by crystallographic studies of bovine cytochrome complex.