Discovery of 6 '-chloro-N-methyl-5 '-(phenylsulfonamido)-[3,3 '-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium
Discovery of 6 '-chloro-N-methyl-5 '-(phenylsulfonamido)-[3,3 '-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium
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DOI：
10.1016/j.ejmech.2019.112012
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发表时间：
2020
影响因子：
6.7
通讯作者：
Liu Qingsong
中科院分区：
文献类型：
--
作者：
Liang Xiaofei;Jiang Zongru;Huang Zhenghui;Li Feng;Chen Cheng;Hu Chen;Wang Wenliang;Hu Zhenquan;Liu Qingwang;Wang Beilei;Wang Li;Qi Ziping;Liu Jing;Jiang Lubin;Liu Qingsong
从联吡啶-磺胺支架开始，药物化学优化导致发现了一种新的恶性疟原虫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（P. falciparum）（EC50: 25.1 nM）具有强效活性。CHMFL-PI4K-127在人脂质和蛋白激酶上对pfpi4k具有高选择性。此外，对一组耐药菌株的ec50值为23 ~ 47 nM。恶性疟原虫。在体内，该抑制剂在大鼠和小鼠体内均表现出良好的药代动力学特性。此外，口服CHMFL-PI4K-127在疟原虫感染的啮齿动物模型的血期（80 mg/kg）和肝期（1 mg/kg）均表现出抗疟效果。结果表明，CHMFL-PI4K-127可能是一种新的潜在候选疟疾药物。
Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound15g(CHMFL-PI4K-127, IC50: 0.9 nM), which exhibits potent activity against 3D7Plasmodium falciparum (P. falciparum)(EC50: 25.1 nM). CHMFL-PI4K-127 displays high selectivity againstPfPI4K over human lipid and protein kinase. In addition, it exhibits EC50values of 23–47 nM against a panel of the drug-resistant strains ofP. 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) ofPlasmodiumin infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.