Exploration and characterization of the antimalarial activity of cyclopropyl carboxamides that target the mitochondrial protein, cytochrome b
- Author(s)
- Awalt, JK; Su, W; Nguyen, W; Loi, K; Jarman, KE; Penington, JS; Ramesh, S; Fairhurst, KJ; Yeo, T; Park, H; Uhlemann, AC; Chandra Maity, B; De, N; Mukherjee, P; Chakraborty, A; CHURCHYARD, A; Famodimu, MT; Delves, MJ; Baum, J; Mittal, N; Winzeler, EA; Papenfuss, AT; Chowdury, M; de Koning-Ward, TF; Maier, AG; van Dooren, GG; Baud, D; Brand, S; Fidock, DA; Jackson, PF; Cowman, AF; Dans, MG; Sleebs, BE;
- Journal Title
- European Journal of Medicinal Chemistry
- 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(50) 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.
- Publisher
- Cell Press
- Keywords
- Antimalarial; Cytochrome b; Malaria; Mitochondria; Plasmodium
- Research Division(s)
- Chemical Biology; Advanced Technology And Biology; Bioinformatics; Infectious Diseases And Immune Defence
- PubMed ID
- 39388903
- Publisher's Version
- https://doi.org/10.1016/j.ejmech.2024.116921
- Open Access at Publisher's Site
https://doi.org/10.1016/j.ejmech.2024.116921- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-10-25 10:15:26
Last Modified: 2024-10-25 10:17:39