7-N-Substituted-3-oxadiazole Quinolones with Potent Antimalarial Activity Target the Cytochrome bc(1) Complex

Nguyen, W; Dans, MG; Currie, I; Awalt, JK; Bailey, BL; Lumb, C; Ngo, A; Favuzza, P; Palandri, J; Ramesh, S; Penington, J; Jarman, KE; Mukherjee, P; Chakraborty, A; Maier, AG; van Dooren, GG; Papenfuss, T; Wittlin, S; CHURCHYARD, A; Baum, J; Winzeler, EA; Baud, D; Brand, S; Jackson, PF; Cowman, AF; Sleebs, BE

Author(s): Nguyen, W; Dans, MG; Currie, I; Awalt, JK; Bailey, BL; Lumb, C; Ngo, A; Favuzza, P; Palandri, J; Ramesh, S; Penington, J; Jarman, KE; Mukherjee, P; Chakraborty, A; Maier, AG; van Dooren, GG; Papenfuss, T; Wittlin, S; CHURCHYARD, A; Baum, J; Winzeler, EA; Baud, D; Brand, S; Jackson, PF; Cowman, AF; Sleebs, BE;
Details: Publication Year 2023-02-28,Volume 9,Issue #3,Page 668-691
Journal Title: ACS Infectious Diseases
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.
Publisher: ACS
Keywords: Plasmodium; antimalarial; cytochrome bc1; malaria; mitochondria
Research Division(s): Chemical Biology; Bioinformatics; Structural Biology; Advanced Technology And Biology; Infectious Diseases And Immune Defence
PubMed ID: 36853190
Publisher's Version: https://doi.org/10.1021/acsinfecdis.2c00607
Open Access at Publisher's Site: https://doi.org/10.1021/acsinfecdis.2c00607
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: acsinfecdis.2c00607.pdf - (4.66MB, application/pdf)

Creation Date: 2023-03-08 03:16:02

Last Modified: 2023-03-15 08:10:03