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Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties

Hong, David, Leung, S, Amporndanai, Kangsa, Davies, Jill, Priestley, Richard, Nixon, Gemma L., Berry, Neil G., Samar Hasnain, S., Antonyuk, Svetlana, Ward, Steve ORCID:, Biagini, Giancarlo ORCID: and O’Neill, Paul M. (2018) 'Potent Antimalarial 2-Pyrazolyl Quinolone bc1 (Qi) Inhibitors with Improved Drug-like Properties'. ACS Medicinal Chemistry Letters, Vol 9, Issue 12, pp. 1205-1210.

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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 bc1 complex, which is supported by crystallographic studies of bovine cytochrome bc1 complex.

Item Type: Article
Subjects: QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials
QV Pharmacology > QV 38 Drug action.
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):
SWORD Depositor: JISC Pubrouter
Depositing User: Stacy Murtagh
Date Deposited: 03 Jan 2019 14:02
Last Modified: 19 Oct 2019 01:02


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