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2-Aryl-3-carbonylquinolones: Design, Synthesis and Biological Evaluation of Novel HCV NS5B Polymerase Inhibitors

文献类型：期刊论文

作者Wang Shenfeng1; Lin Jianping1; He Peilan2; Zuo Jianping2; Long Yaqiu1
刊名ACTA CHIMICA SINICA
出版日期2014-08-15
卷号72期号:8页码:906-913
关键词HCV NS5B polymerase 2-substituted quinolone-3-carboxylic acid non-nucleoside inhibitor direct acting antiviral allosteric site
ISSN号0567-7351
DOI10.6023/A14060431
文献子类Article
英文摘要Hepatitis C virus (HCV) infection is a global health problem that impacts approximately 180 million individuals. Until recently the current therapy for treating HCV infection has been regular injections of pegalated a-interferon (PEG-IFN) with daily oral administration of ribavirin (RBV). However, PEG-IFN/RBV treatment is only effective for only 50% of genotype 1 patients and associated with significant adverse effects including fatigue, hemolytic anemia, depression, and flu-like symptoms. Therefore, the search for direct acting antivirals (DAAs) that are safe and effective has become an urgent endeavor. HCV NS5B polymerase, an essential enzyme for the HCV RNA replication, has emerged as an attractive and validated target for the direct HCV therapeutic intervention. Since NS5B polymerase needs a divalent metal ion as a cofactore in the active site for its catalytic function, the metal chelation motif-containing quinolone-3-carboxylic scaffold has been explored as a new class of non-nucleoside NS5B inhibitors. Two groups have recently reported a preliminary structure-activity relationship (SAR) study on the 4-quinolone-3-carboxylic acids as HCV NS5B inhibitors, just focused on the N-1, C-3 and C-6/7 substitutions. Based on the binding mode revealed by the cocrystal structure of the quinolone inhibitor bound to the NS5B enzyme, for the first time we proposed to introduce a hydrophobic group at C-2 position on the quinolone ring to improve the anti-HCV potency. By making use of the new method to synthesize 2-substituted quinolone-3-carboxylic acid derivatives recently developed by our group, we conducted a comprehensive SAR study on the 2-aryl-3-carbonylquinolone-based non-nucleoside inhibitors of HCV NS5B polymerase. Starting from the readily accessible amides and 3-oxo-3-arylpropanoates, structurally diverse 2-substituted quinolone-3-carboxylic acid derivatives were efficiently furnished by a tandem addition-elimination reaction/nucleophilic aromatic substitution reaction via an imine-enamine intermediate. The anti-HCV potency and cytotoxicity were evaluated in the HCV-infected host cells Huh7.5.1 assay system. To our delight, the incorporation of a hydrophobic aryl group into 2-position of the quinolone core really enhanced the inhibitory activity against the HCV replication in the host cells with a 2-fold selectivity over the cytotoxicity. Meanwhile, a small size hydrophobic group at N-1 position was favored for the 2-arylquinolone-derived NS5B inhibitors. Further structural variation was investigated on the C-3 and C-7 substituents, with an aromatic ester and an N-methyl piperazine being an optimal moiety, respectively. The global structural optimization at positions N-1, C-2, C-3 and C-7 resulted in the discovery of novel 2-aryl substituted quinolone inhibitors with low micromolar EC50 values to inhibit the replication of the HCV RNA in the host cell Huh7.5.1 and therapeutic indices of 2 similar to 6, providing a new promising lead for the further development into anti-HCV drug candidates.
WOS关键词HEPATITIS-C VIRUS ; HIV-1 INTEGRASE INHIBITORS ; INFECTION ; NUCLEOTIDE ; SCAFFOLD ; SOFOSBUVIR ; DISCOVERY ; LEDGF/P75 ; ACIDS
资助项目National Natural Science Foundation of China[81325020] ; National Natural Science Foundation of China[81361120410]
WOS研究方向Chemistry
语种中文
CSCD记录号CSCD:5211739
WOS记录号WOS:000340842200002
出版者SCIENCE PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/276939]  
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
药物化学研究室
通讯作者Wang Shenfeng
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		 Wang Shenfeng,Lin Jianping,He Peilan,et al. 2-Aryl-3-carbonylquinolones: Design, Synthesis and Biological Evaluation of Novel HCV NS5B Polymerase Inhibitors[J]. ACTA CHIMICA SINICA,2014,72(8):906-913.
APA Wang Shenfeng,Lin Jianping,He Peilan,Zuo Jianping,&Long Yaqiu.(2014).2-Aryl-3-carbonylquinolones: Design, Synthesis and Biological Evaluation of Novel HCV NS5B Polymerase Inhibitors.ACTA CHIMICA SINICA,72(8),906-913.
MLA Wang Shenfeng,et al."2-Aryl-3-carbonylquinolones: Design, Synthesis and Biological Evaluation of Novel HCV NS5B Polymerase Inhibitors".ACTA CHIMICA SINICA 72.8(2014):906-913.

入库方式： OAI收割

来源：上海药物研究所

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