A series of 2-pyrazolyl quinolones has been designed and synthesized in 5-7 steps to optimize for both <i>in vitro</i> antimalarial potency and various <i>in vitro</i> 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<sub>50</sub> (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 <i>in vitro</i> cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Q<sub>i</sub> site of the parasite <i>bc</i> <sub>1</sub> complex, which is supported by crystallographic studies of bovine cytochrome <i>bc</i> <sub>1</sub> complex.