New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2
New 1-phenyl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2
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DOI：
10.1016/j.ejmech.2014.11.042
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发表时间：
2015-01-27
影响因子：
6.7
通讯作者：
Silvestri, Romano
中科院分区：
文献类型：
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作者：
Manvar, Dinesh;Pelliccia, Sveva;Silvestri, Romano
本文报道了一类新型HCV抑制剂吡唑甲酰胺衍生物的合成及其抑制机制。化合物6、7、8和16抑制HCV复制子lb基因型的EC50值在5 ~ 8 μ M之间，对传染性Jc1型HCV 2a基因型表现出更高的抑制效力。化合物6对HCV 1b的EC50值为6.7 μ M，选择性指数为23，在7 μ M处使感染性Jc1嵌合2a克隆的RNA拷贝数减少82%，抗HCV活性模式评估显示，化合物6抑制HCV诱导的COX-2 mRNA和蛋白表达，在COX-2启动子连锁荧光素酶报告基因试验中显示IC50值为3.2 μ M。相反，当COX-2过表达时，6的抗hcv活性被消除。这些发现表明，6作为这些吡唑羧基酰胺的代表，通过在转录和翻译水平上靶向COX-2而发挥抗hcv药物的作用。(C) 2014 Elsevier Masson SAS。版权所有。
We report here the synthesis and mechanism of inhibition of pyrazolecarboxamide derivatives as a new class of HCV inhibitors. Compounds 6, 7, 8 and 16 inhibited the subgenomic HCV replicon lb genotype at EC50 values between 5 and 8 mu M and displayed an even higher potency against the infectious Jc1 HCV 2a genotype. Compound 6 exhibited an EC50 of 6.7 mu M and selectivity index of 23 against HCV 1b, and reduced the RNA copies of the infectious Jc1 chimeric 2a clone by 82% at 7 mu M. Evaluation of the mode of anti-HCV activity of 6 revealed that it suppressed HCV-induced COX-2 mRNA and protein expression, displaying an IC50 of 3.2 mu M in COX-2 promoter-linked luciferase reporter assay. Conversely, the anti-HCV activity of 6 was abrogated upon over-expression of COX-2. These findings suggest that 6 as a representative of these pyrazolecarboxamides function as anti-HCV agents via targeting COX-2 at both the transcription and translation levels. (C) 2014 Elsevier Masson SAS. All rights reserved.