6HAW

Crystal structure of bovine cytochrome bc1 in complex with 2-pyrazolyl quinolone inhibitor WDH2G7

Summary for 6HAW

• Entry DOI: 10.2210/pdb6haw/pdb
• Descriptor: Cytochrome b-c1 complex subunit 1, mitochondrial, Cytochrome b-c1 complex subunit 9, 1,2-DIHEXANOYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE, ... (24 entities in total)
• Functional Keywords: cytochrome bc1, malaria, electron transport
• Biological source: Bos taurus (cattle); More
• Total number of polymer chains: 10
• Total formula weight: 238530.04

Authors

Amporndanai, K.,Hong, W.D.,O'Neill, P.M.,Hasnain, S.S.,Antonyuk, S.V. (deposition date: 2018-08-08, release date: 2019-01-16, Last modification date: 2024-01-17)

Primary citation

David Hong, W.,Leung, S.C.,Amporndanai, K.,Davies, J.,Priestley, R.S.,Nixon, G.L.,Berry, N.G.,Samar Hasnain, S.,Antonyuk, S.,Ward, S.A.,Biagini, G.A.,O'Neill, P.M.
Potent Antimalarial 2-Pyrazolyl Quinolonebc1(Qi) Inhibitors with Improved Drug-like Properties.
ACS Med Chem Lett, 9:1205-1210, 2018

PubMed Abstract: 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.

PubMed: 30613327
DOI: 10.1021/acsmedchemlett.8b00371

Experimental method

X-RAY DIFFRACTION (3.45 Å)