Calit Juliana, Prajapati Surendra K, Benavente Ernest D, Araújo Jessica E, Deng Bingbing, Miura Kazutoyo, Annunciato Yasmin, Moura Igor M R, Usui Miho, Medeiros Jansen F, Andrade Carolina H, Silva-Mendonça Sabrina, Simeonov Anton, Eastman Richard T, Long Carole A, da Silva Araujo Maisa, Williamson Kim C, Aguiar Anna Caroline C, Bargieri Daniel Y
Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-000, Brazil.
Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4712, United States.
JACS Au. 2024 Oct 7;4(10):3942-3952. doi: 10.1021/jacsau.4c00674. eCollection 2024 Oct 28.
Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic line was used to perform a series of high-throughput in vitro screens for new antimalarials acting against the parasite sexual stages. The screens identified pyrimidine azepine chemotypes with potent activity. Here, we validate the activity of , the most potent pyrimidine azepine chemotype identified, against and in the asexual and sexual stages. blocked parasite transmission to the mosquito vector at nanomolar concentrations and inhibited in vitro asexual parasite multiplication with a fast-action profile. Through the generation of resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome as a molecular target of . This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the cytochrome complex.
疟疾控制和消除工作将受益于新的疟疾化疗药物的鉴定和验证。最近，一个转基因品系被用于对作用于疟原虫有性阶段的新型抗疟药进行一系列高通量体外筛选。这些筛选鉴定出了具有强效活性的嘧啶氮杂䓬化学类型。在此，我们验证了所鉴定出的最具活性的嘧啶氮杂䓬化学类型对无性和有性阶段的疟原虫及疟原虫的活性。该化合物在纳摩尔浓度下阻断了寄生虫向蚊媒的传播，并以快速作用模式抑制了体外无性寄生虫的增殖。通过产生对该化合物耐药的寄生虫并进行线粒体活性的体外测定，我们确定细胞色素b为该化合物的分子靶点。这项工作描述了一种有前景的化学类型，可用于未来开发针对细胞色素b复合物的新型抗疟药。
