Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b

Published in : European Journal of Medicinal Chemistry Volume 280, 15 December 2024, 116921

DOI : 10.1016/j.ejmech.2024.116921

Authors : Jon Kyle Awalt, Wenyin Su, William Nguyen, Katie Loi, Kate E. Jarman, Jocelyn S. Penington, Saishyam Ramesh, Kate J. Fairhurst, Tomas Yeo, Heekuk Park, Anne-Catrin Uhlemann, Bikash ChandraMaity [TCGLS Member], Nirupam De [TCGLS Member], Partha Mukherjee [TCGLS Member], Arnish Chakraborty [TCGLS Member], Alisje Churchyard, Mufuliat T. Famodimu, MichaelJ. Delves, Jake Baum, Nimisha Mittal…Brad E. Sleebs

Abstract : Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC₅₀ 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype.