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Potent Antimalarial 2-Pyrazolyl Quinolone bc 1 (Qi) 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 through in vitro cytotoxicity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc 1 complex, which is supported by crystallographic studies of bovine cytochrome bc 1 complex.

SUBMITTER: David Hong W 

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

REPOSITORIES: biostudies-literature

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

David Hong W W   Leung Suet C SC   Amporndanai Kangsa K   Davies Jill J   Priestley Richard S RS   Nixon Gemma L GL   Berry Neil G NG   Samar Hasnain S S   Antonyuk Svetlana S   Ward Stephen A SA   Biagini Giancarlo A GA   O'Neill Paul M PM  

ACS medicinal chemistry letters 20181019 12

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. Furth  ...[more]

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