Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.
Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.
复制标题
发现基于咪唑的恶性疟原虫 cGMP 依赖性蛋白激酶抑制剂。
DOI：
10.1021/acsmedchemlett.1c00540
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发表时间：
2021
影响因子：
4.2
通讯作者：
Sie
中科院分区：
文献类型：
--
作者：
Bheemanaboina,RammohanRYadav;deSouza,MarianaLaureano;Gonzalez,MarianaLozano;Mahmood,ShamsUl;Eck,Tyler;Kreiss,Tamara;Aylor,SamanthaO;Roth,Alison;Lee,Patricia;Pybus,BrandonS;Colussi,DennisJ;Childers,WayneE;Gordon,John;Sie
随着口服恶性疟原虫cgmp依赖性蛋白激酶（PfPKG）抑制剂可以清除小鼠模型中的感染，治疗疟疾的新靶点的发现，特别是那些针对生命周期中红细胞前阶段的靶点的发现取得了进展。这种热情被这些化学型不令人满意的安全性和/或药代动力学问题所缓和。为了解决对新型支架的迫切需求，本文介绍了咪唑支架在四个位置的初始结构-活性关系，具有代表性的vitroADME， hERG表征以及基于细胞的抗寄生虫活性。该系列PfPKG抑制剂具有良好的体外PfPKG效价，低hERG活性，并且对多种疟原虫具有基于细胞的抗寄生活性，这似乎与它们的体外效价相关。
The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors ofPlasmodium falciparumcGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure–activity relationships in an imidazole scaffold at four positions, representativein vitroADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has goodin vitroPfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiplePlasmodiumspecies that appears to be correlated with thein vitropotency.