The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, 3010, Australia.
The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia.
Eur J Med Chem. 2024 Dec 15;280:116921. doi: 10.1016/j.ejmech.2024.116921. Epub 2024 Oct 3.
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 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.
抗疟药物的耐药性使其疗效逐渐降低，因此需要开发新的抗疟药物。为了发现新的抗疟化学类型，对詹森启动子库进行了针对疟原虫无性阶段的表型筛选，发现了环丙基羧酰胺结构命中类。结构活性分析表明，每个结构部分都基本不能改变，尽管小的变化导致了前导化合物 WJM280 的产生，它具有很强的无性阶段活性（EC 40 nM），并且对人细胞没有细胞毒性。正向遗传学发现，环丙基羧酰胺抗性寄生虫在细胞色素 b 基因中发生突变和扩增。随后，细胞色素 b 被证实是该药物的靶标，通过针对细胞色素 b 耐药寄生虫的药物分析和线粒体耗氧测定进行了验证。因此，环丙基羧酰胺类药物具有缓慢作用的无性阶段活性，以及对雄性配子和红细胞外期的活性。在未来开发这种抗疟化学类型时，提高代谢稳定性以达到疟疾小鼠模型的疗效仍然是一个挑战。
