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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

文献类型：期刊论文

作者Liang, Xiaofei4; Jiang, Zongru4,5; Huang, Zhenghui1; Li, Feng4,5; Chen, Cheng4,5; Hu, Chen4; Wang, Wenliang4,5; Hu, Zhenquan4; Liu, Qingwang6; Wang, Beilei4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2020-02-15
卷号188
关键词PI4K kinase Kinase inhibitor Malaria Blood stage Liver stage
ISSN号0223-5234
DOI10.1016/j.ejmech.2019.112012
通讯作者Liu, Jing(jingliu@hmfl.ac.cn) ; Jiang, Lubin(lbjiang@ips.ac.cn) ; Liu, Qingsong(qsliu97@hmfl.ac.cn)
英文摘要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. (C) 2019 Elsevier Masson SAS. All rights reserved.
WOS关键词DRUG CANDIDATE ; RESISTANCE ; CYNOMOLGI ; MECHANISM ; BERGHEI ; AGENT
资助项目National Natural Science Foundation of China[81872745] ; National Natural Science Foundation of China[81773777] ; National Natural Science Foundation of China[81872748] ; National Natural Science Foundation of China[31771455] ; National Natural Science Foundation of China[81271863] ; National Key Research and Development Program of China[2016YFA0400900] ; Natural Science Foundation of Anhui Province[1908085QH348] ; China Postdoctoral Science Foundation[2019M652057] ; Frontier Science Key Research Program of CAS[QYZDB-SSW-SLH037] ; Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology[2018CXFX008] ; University Synergy Innovation Program of Anhui Province[OM-2019-045] ; CASHIPS Director's Fund[BJPY2019A03] ; Key Program of 13th five-year plan of CASHIPS[KP-2017-26] ; Youth Innovation Promotion Association of CAS[2016385] ; High Magnetic Field Laboratory of Anhui Province
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000515428100023
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
资助机构National Natural Science Foundation of China ; National Key Research and Development Program of China ; Natural Science Foundation of Anhui Province ; China Postdoctoral Science Foundation ; Frontier Science Key Research Program of CAS ; Innovative Program of Development Foundation of Hefei Center for Physical Science and Technology ; University Synergy Innovation Program of Anhui Province ; CASHIPS Director's Fund ; Key Program of 13th five-year plan of CASHIPS ; Youth Innovation Promotion Association of CAS ; High Magnetic Field Laboratory of Anhui Province
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/103949]  
专题中国科学院合肥物质科学研究院
通讯作者Liu, Jing; Jiang, Lubin; Liu, Qingsong
作者单位1.Chinese Acad Sci, Univ Chinese Acad Sci, Inst Pasteur Shanghai, Unit Human Parasite Mol & Cell Biol,Key Lab Mol V, Shanghai 200031, Peoples R China
2.Anhui Univ, Inst Phys Sci, Hefei 230601, Anhui, Peoples R China
3.Anhui Univ, Inst Informat Technol, Hefei 230601, Anhui, Peoples R China
4.Chinese Acad Sci, Hefei Inst Phys Sci, High Magnet Field Lab, Key Lab High Magnet Field & Ion Beam Phys Biol, Hefei 230031, Anhui, Peoples R China
5.Univ Sci & Technol China, Hefei 230026, Anhui, Peoples R China
6.Chinese Acad Sci, Hefei Inst Phys Sci, Precis Targeted Therapy Discovery Ctr, Inst Technol Innovat, Hefei 230088, Anhui, Peoples R China
推荐引用方式
GB/T 7714		 Liang, Xiaofei,Jiang, Zongru,Huang, Zhenghui,et al. 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[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,188.
APA Liang, Xiaofei.,Jiang, Zongru.,Huang, Zhenghui.,Li, Feng.,Chen, Cheng.,...&Liu, Qingsong.(2020).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.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,188.
MLA Liang, Xiaofei,et al."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".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 188(2020).

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来源：合肥物质科学研究院

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