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Potent antimalarial 2-pyrazoyl quinolone bc1 (Qi) inhibitors with improved drug-like properties

DOI: 10.1021/acsmedchemlett.8b00371 DOI Help

Authors: Weiqian David Hong (University of Liverpool) , Suet C. Leung (Liverpool School of Tropical Medicine) , Kangsa Amporndanai (University of Liverpool) , Jill Davies (Liverpool School of Tropical Medicine) , Richard S. Priestley (Liverpool School of Tropical Medicine) , Gemma Louise Nixon (University of Liverpool) , Neil G. Berry (University of Liverpool) , S. Samar Hasnain (University of Liverpool) , Svetlana Antonyuk (University of Liverpool) , Stephen A. Ward (Liverpool School of Tropical Medicine) , Giancarlo A. Biagini (Liverpool School of Tropical Medicine) , Paul O'neill (University of Liverpool)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters

State: Published (Approved)
Published: October 2018
Diamond Proposal Number(s): 11740

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 multi-drug 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 acceptbale safety margin through in vitro cytotocity assessment. The 2-pyrazolyl quinolones are believed to bind to the ubiquinone-reducing Qi site of the parasite bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.

Journal Keywords: Quinolone; Antimalarial; Plasmodium falciparum; Cytochrome bc1; atovaquone; drug resistance

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography