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

Autor: Nguyen W; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Dans MG; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Currie I; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Awalt JK; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Bailey BL; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Lumb C; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia., Ngo A; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia., Favuzza P; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Palandri J; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Ramesh S; Research School of Biology, The Australian National University, Canberra 2600, Australia., Penington J; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Jarman KE; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Mukherjee P; TCG Lifesciences, Kolkata, West Bengal 700091, India., Chakraborty A; TCG Lifesciences, Kolkata, West Bengal 700091, India., Maier AG; Research School of Biology, The Australian National University, Canberra 2600, Australia., van Dooren GG; Research School of Biology, The Australian National University, Canberra 2600, Australia., Papenfuss T; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Wittlin S; Swiss Tropical and Public Health Institute, Kreuzstrasse 2, 4123 Allschwil, Switzerland.; University of Basel, 4003 Basel, Switzerland., Churchyard A; Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ U.K., Baum J; Department of Life Sciences, Imperial College London, South Kensington, SW7 2AZ U.K.; School of Biomedical Sciences, University of New South Wales, Sydney 2031, Australia., Winzeler EA; School of Medicine, University of California San Diego, 9500 Gilman Drive 0760, La Jolla, California 92093, United States., Baud D; Medicines for Malaria Venture, Geneva 1215, Switzerland., Brand S; Medicines for Malaria Venture, Geneva 1215, Switzerland., Jackson PF; Global Public Health, Janssen R&D LLC, La Jolla, California 92121, United States., Cowman AF; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia., Sleebs BE; The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.; Department of Medical Biology, The University of Melbourne, Parkville 3010, Australia.
Jazyk: angličtina
Zdroj: ACS infectious diseases [ACS Infect Dis] 2023 Mar 10; Vol. 9 (3), pp. 668-691. Date of Electronic Publication: 2023 Feb 28.
DOI: 10.1021/acsinfecdis.2c00607
Abstrakt: 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.
Databáze: MEDLINE