2芳基3羰基喹诺酮新型hcvns5b多聚酶抑制剂的设计合成和活性评估

doi:10.6023/A14060431

	2芳基3羰基喹诺酮新型hcvns5b多聚酶抑制剂的设计合成和活性评估
	王沈丰; 林建平; 何佩岚; 左建平; 龙亚秋
刊名	化学学报
	2014
卷号	72 期号:8 页码:906
关键词	HEPATITIS-C VIRUS HIV-1 INTEGRASE INHIBITORS INFECTION NUCLEOTIDE SCAFFOLD SOFOSBUVIR DISCOVERY LEDGF/P75 ACIDS HCV NS5B polymerase 2-substituted quinolone-3-carboxylic acid non-nucleoside inhibitor direct acting antiviral allosteric site
ISSN号	0567-7351
DOI	10.6023/A14060431
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.
资助项目	[National Natural Science Foundation of China]
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/283961]
专题	中国科学院上海药物研究所
作者单位	中国科学院上海药物研究所
推荐引用方式 GB/T 7714	王沈丰,林建平,何佩岚,等. 2芳基3羰基喹诺酮新型hcvns5b多聚酶抑制剂的设计合成和活性评估[J]. 化学学报,2014,72(8):906.
APA	王沈丰,林建平,何佩岚,左建平,&龙亚秋.(2014).2芳基3羰基喹诺酮新型hcvns5b多聚酶抑制剂的设计合成和活性评估.化学学报,72(8),906.
MLA	王沈丰,et al."2芳基3羰基喹诺酮新型hcvns5b多聚酶抑制剂的设计合成和活性评估".化学学报 72.8(2014):906.