biostudies-literatureAwalt JKMedicines for Malaria VentureNIAID NIH HHSNational Health and Medical Research CouncilNational Institutes of HealthWellcome Trust116921https://www.ebi.ac.uk/biostudies/studies/S-EPMC11609934biostudies-literatureUnknown280Drug 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.European journal of medicinal chemistryExploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b.PMC11609934R01 AI152533Jackson PFDelves MJMaier AGFairhurst KJde Koning-Ward TFFidock DAUhlemann ACChowdury MBaum JCowman AFRamesh SSleebs BEWinzeler EASu WNguyen WYeo TPark HPapenfuss ATDans MGChakraborty AFamodimu MTDe NAwalt JKJarman KELoi KBrand SChurchyard Avan Dooren GGMukherjee PPenington JSChandra Maity BMittal NBaud DfalseExploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b.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.2024-01-01T00:00:00Z2024 Dec2026-06-03T00:50:19.264Z2026-04-22T03:11:58.851ZS-EPMC116099343938890310.1016/j.ejmech.2024.116921