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7-N-substituted-3-oxadiazole quinolones with potent antimalarial activity target the cytochrome bc1 complex

Nguyen, W. and Dans, M. G. and Currie, I. and Awalt, J. K. and Bailey, B. L. and Lumb, C. and Ngo, A. and Favuzza, P. and Palandri, J. and Ramesh, S. and Penington, J. and Jarman, K. E. and Mukherjee, P. and Chakraborty, A. and Maier, A. G. and van Dooren, G. G. and Papenfuss, T. and Wittlin, S. and Churchyard, A. and Baum, J. and Winzeler, E. A. and Baud, D. and Brand, S. and Jackson, P. F. and Cowman, A. F. and Sleebs, B. E.. (2023) 7-N-substituted-3-oxadiazole quinolones with potent antimalarial activity target the cytochrome bc1 complex. ACS Infect Dis, 9 (3). pp. 668-691.

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Official URL: https://edoc.unibas.ch/94553/

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Abstract

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies. To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7-N-substituted-3-oxadiazole quinolone hit class. We established the structure-activity relationship and optimized the antimalarial potency. The optimized analog WJM228 (17) showed robust metabolic stability in vitro, although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Q(o) site of cytochrome b (cyt b), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Q(o) site but not Q(i) site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b. Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Q(o) site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Wittlin, Sergio
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:2373-8227 (Electronic)2373-8227 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:09 May 2023 06:52
Deposited On:09 May 2023 06:52

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