Pyrimidine Azepine Targets the Plasmodium bc 1 Complex and Displays Multistage Antimalarial Activity.

IF 8.5 Q1 CHEMISTRY, MULTIDISCIPLINARY JACS Au Pub Date : 2024-10-07 eCollection Date: 2024-10-28 DOI:10.1021/jacsau.4c00674
Juliana Calit, Surendra K Prajapati, Ernest D Benavente, Jessica E Araújo, Bingbing Deng, Kazutoyo Miura, Yasmin Annunciato, Igor M R Moura, Miho Usui, Jansen F Medeiros, Carolina H Andrade, Sabrina Silva-Mendonça, Anton Simeonov, Richard T Eastman, Carole A Long, Maisa da Silva Araujo, Kim C Williamson, Anna Caroline C Aguiar, Daniel Y Bargieri
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Abstract

Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic Plasmodium berghei 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 PyAz90, the most potent pyrimidine azepine chemotype identified, against P. falciparum and P. vivax in the asexual and sexual stages. PyAz90 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 P. falciparum PyAz90-resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome b as a molecular target of PyAz90. This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the Plasmodium cytochrome bc 1 complex.

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嘧啶氮杂环庚烷以疟原虫 bc 1 复合物为靶标,发挥多级抗疟活性
疟疾控制和消除工作将受益于新疟疾化疗药物的鉴定和验证。最近,我们利用转基因疟原虫品系进行了一系列高通量体外筛选,以寻找针对寄生虫有性阶段的新型抗疟药物。这些筛选确定了具有强效活性的嘧啶氮杂环庚烷化学型。在这里,我们验证了 PyAz90 的活性,它是已发现的最有效的嘧啶氮杂环庚烷化学型,对恶性疟原虫和间日疟原虫的无性阶段和有性阶段均有作用。PyAz90 在纳摩尔浓度下可阻断寄生虫向蚊媒的传播,并能快速抑制体外无性寄生虫的繁殖。通过产生恶性疟原虫 PyAz90 抗性寄生虫和线粒体活性体外检测,我们确定细胞色素 b 是 PyAz90 的分子靶标。这项工作描述了一种很有前景的化学类型,可用于今后开发针对疟原虫细胞色素 bc 1 复合物的新型抗疟药。
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