{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Awalt JK"],"funding":["Medicines for Malaria Venture","NIAID NIH HHS","National Health and Medical Research Council","National Institutes of Health","Wellcome Trust"],"pagination":["116921"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11609934"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["280"],"pubmed_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 (EC<sub>50</sub> 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."],"journal":["European journal of medicinal chemistry"],"pubmed_title":["Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b."],"pmcid":["PMC11609934"],"funding_grant_id":["R01 AI152533"],"pubmed_authors":["Jackson PF","Delves MJ","Maier AG","Fairhurst KJ","de Koning-Ward TF","Fidock DA","Uhlemann AC","Chowdury M","Baum J","Cowman AF","Ramesh S","Sleebs BE","Winzeler EA","Su W","Nguyen W","Yeo T","Park H","Papenfuss AT","Dans MG","Chakraborty A","Famodimu MT","De N","Awalt JK","Jarman KE","Loi K","Brand S","Churchyard A","van Dooren GG","Mukherjee P","Penington JS","Chandra Maity B","Mittal N","Baud D"],"additional_accession":[]},"is_claimable":false,"name":"Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b.","description":"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 (EC<sub>50</sub> 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Dec","modification":"2026-06-03T00:50:19.264Z","creation":"2026-04-22T03:11:58.851Z"},"accession":"S-EPMC11609934","cross_references":{"pubmed":["39388903"],"doi":["10.1016/j.ejmech.2024.116921"]}}