Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC50 values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.

中文翻译：

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发现6'-氯-N-甲基-5'-（苯磺酰胺基）-[3,3'-联吡啶] -5-羧酰胺（CHMFL-PI4K-127）作为新型恶性疟原虫PI（4）K抑制剂对疟原虫的血液和肝脏阶段均具有抗疟疾活性。

从联吡啶-磺酰胺支架开始，药物化学优化导致发现新的恶性疟原虫PI4K激酶（PfPI4K）抑制剂化合物15g（CHMFL-PI4K-127，IC50：0.9 nM），该化合物对3D7恶性疟原虫（（恶性疟原虫（EC50：25.1 nM）。CHMFL-PI4K-127对PfPI4K的选择性高于对人脂质和蛋白激酶的选择性。此外，针对恶性疟原虫的一系列耐药菌株，其EC50值为23-47 nM。在体内，该抑制剂在大鼠和小鼠中均显示出良好的药代动力学特性。此外，在感染的啮齿动物模型中，口服CHMFL-PI4K-127在疟原虫的血液阶段（80 mg / kg）和肝脏阶段（1 mg / kg）均显示出抗疟疾功效。