C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus
C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus
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DOI：
10.1016/j.bmc.2012.05.066
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发表时间：
2012-08-01
影响因子：
3.5
通讯作者：
Wang, Zhengqiang
中科院分区：
文献类型：
--
作者：
Chen, Yue-Lei;Zacharias, Jeana;Wang, Zhengqiang
喹诺酮-3-羧酸在药物化学中代表高度特权的化学型，并且已经被广泛地探索为靶向人类免疫缺陷病毒（HIV）整合酶（IN）的抗生素和抗病毒药。本文报道了一系列C-6芳基取代的4-喹啉酮-3-羧酸类似物的合成及其抗丙型肝炎病毒（HCV）活性。在细胞培养物中观察到低微摩尔范围的几种类似物对HCV复制子的显著抑制，并通过RT-qPCR测定证实了复制子RNA的减少。有趣的是，在生化测定中对类似物作为NS 5 B抑制剂的评估仅产生了适度的抑制活性，这表明在细胞培养中可能存在不同的作用机制。(C)2012爱思唯尔有限公司保留所有权利。
Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture. (C) 2012 Elsevier Ltd. All rights reserved.