Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency

doi:10.1016/j.bmcl.2016.04.042

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency
	Cheng, Yu 1; Shen, Jian 2; Peng, Run-Ze 1; Wang, Gui-Feng2 ; Zuo, Jian-Ping2 ; Long, Ya-Qiu 1
刊名	BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
	2016-06-15
卷号	26 期号:12 页码:2900-2906
关键词	HCV NS5B polymerase 2-Alkyl quinolone 1,6-Naphthyridine-4,5-dione Non-nucleoside inhibitor Direct acting antiviral Allosteric site
ISSN号	0960-894X
DOI	10.1016/j.bmcl.2016.04.042
文献子类	Article
英文摘要	HCV NS5B polymerase is an attractive and validated target for anti-HCV therapy. Starting from our previously identified 2-aryl quinolones as novel non-nucleoside NS5B polymerase inhibitors, structure-based optimization furnished 2-alkyl-N-benzyl quinolones with improved antiviral potency by employing privileged fragment hybridization strategy. The N-(4-chlorobenzyl)-2-(methoxymethyl) quinolone derivative 5f proved to be the best compound of this series, exhibiting a selective sub-micromolar antiviral effect (EC50 = 0.4 mu M, SI = 10.8) in Huh7.5.1 cells carrying a HCV genotype 2a. Considering the undesirable pharmacokinetic property of the highly substituted quinolones, a novel chemotype of 1,6-naphthyridine-4,5-diones were evolved via scaffold hopping, affording brand new structure HCV inhibitors with compound 6h (EC50 (gt2a) = 2.5 mu M, SI = 7.2) as a promising hit. Molecular modeling studies suggest that both of 2-alkyl quinolones and 1,6-naphthyridine-4,5-diones function as HCV NS5B thumb pocket II inhibitors. (C) 2016 Elsevier Ltd. All rights reserved.
资助项目	National Science Foundation of China[81325020] ; National Science Foundation of China[81361120410] ; National Science Foundation of China[81321092] ; National Program on Key Basic Research Project of China[2013CB911104]
WOS关键词	HEPATITIS-C VIRUS ; DEPENDENT RNA-POLYMERASE ; PROTEASE INHIBITOR ; DISCOVERY ; IDENTIFICATION ; NUCLEOTIDE ; STRATEGIES ; MORTALITY ; REVEALS ; UPDATE
WOS研究方向	Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000376728200032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276003]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zuo, Jian-Ping; Long, Ya-Qiu
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Cheng, Yu,Shen, Jian,Peng, Run-Ze,et al. Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,2016,26(12):2900-2906.
APA	Cheng, Yu,Shen, Jian,Peng, Run-Ze,Wang, Gui-Feng,Zuo, Jian-Ping,&Long, Ya-Qiu.(2016).Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency.BIOORGANIC & MEDICINAL CHEMISTRY LETTERS,26(12),2900-2906.
MLA	Cheng, Yu,et al."Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency".BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 26.12(2016):2900-2906.