The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus
The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus
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DOI：
10.1016/j.bmc.2011.10.058
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发表时间：
2012-01-01
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;Tang, Jing;Wang, Zhengqiang
C7取代的2-羟基异喹啉-1，3-二酮抑制HIV整合酶(IN)和逆转录酶相关核糖核酸酶H(RNH)的链转移。丙型肝炎病毒(丙型肝炎病毒)NS5B聚合酶与RNH和IN有相似的活性部位折叠，提示N-羟基亚胺可能通过靶向NS5B而成为有用的丙型肝炎病毒抑制剂支架。本文介绍了C-6或C-7芳基取代的2-羟基异喹啉-1，3-二酮作为新型丙型肝炎病毒抑制剂的设计、化学合成、复制子和生化分析以及分子对接。该合成包括一种改进的清洁的环化方法，这使得各种类似物的制备变得方便。生物学研究表明，C-6类似物是一种未知的化学类型，在低微摩尔范围内持续抑制丙型肝炎病毒复制子和重组NS5B。分子模拟研究表明，这些抑制剂可能与NS5B活性部位结合。(C)2011爱思唯尔有限公司。保留所有权利。
C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site. (C) 2011 Elsevier Ltd. All rights reserved.