Development of a class of bicyclic inhibitors of the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG), starting from known compounds with activity against a related parasite PKG orthologue, is reported. Examination of key sub-structural elements led to new compounds with good levels of inhibitory activity against the recombinant kinase and in vitro activity against the parasite. Key examples were shown to possess encouraging in vitro ADME properties, and computational analysis provided valuable insight into the origins of the observed activity profiles.

中文翻译：

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疟疾恶性疟原虫蛋白激酶 G 的强效抑制剂：提高一系列咪唑并吡啶类药物的细胞活性。

据报道，从具有抗相关寄生虫 PKG 直向同源物活性的已知化合物开始，开发了一类恶性疟原虫环 GMP 依赖性蛋白激酶 (PfPKG) 的双环抑制剂。对关键亚结构元件的检查产生了对重组激酶具有良好水平的抑制活性以及对寄生虫具有体外活性的新化合物。关键示例被证明具有令人鼓舞的体外 ADME 特性，计算分析为观察到的活性概况的起源提供了宝贵的见解。