Mahboubi Rabbani Sayyed Mohammad Ismaeil, Vahabpour Rouhollah, Hajimahdi Zahra, Zarghi Afshin
Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Medical Lab Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Iran J Pharm Res. 2019 Fall;18(4):1790-1802. doi: 10.22037/ijpr.2019.112186.13586.
HCV-induced hepatitis is one of the most debilitating diseases. The limited number of anti-HCV drugs and drug-resistance necessitate developing of new scaffolds with different mode of actions. HCV non-structural protein 5B (NS5B) is an attractive target for development of novel inhibitors of HCV replication. In this paper, new N'-arylidene-6-(benzyloxy)-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives were designed based on the pharmacophores of HCV NS5B active site binding inhibitors. Designed compounds were synthesized and evaluated for their inhibitory activities in a cell-based HCV replicon system assay. Among tested compounds, compounds and were found to be the most active (EC = 35 and 70 µM, respectively) with good selectivity index (SI > 2) in the corresponding series. Molecular modeling studies showed that the designed compounds are capable of forming key coordination with the two magnesium ions as well as interactions with other key residues at the active site of HCV NS5B.
丙型肝炎病毒（HCV）引起的肝炎是最具致残性的疾病之一。抗HCV药物数量有限且存在耐药性，因此有必要开发具有不同作用方式的新支架。HCV非结构蛋白5B（NS5B）是开发新型HCV复制抑制剂的一个有吸引力的靶点。本文基于HCV NS5B活性位点结合抑制剂的药效团设计了新型N'-亚芳基-6-（苄氧基）-4-氧代-1,4-二氢喹啉-3-碳酰肼衍生物。合成了设计的化合物，并在基于细胞的HCV复制子系统测定中评估了它们的抑制活性。在测试的化合物中，化合物 和 被发现活性最高（EC分别为35和70 μM），在相应系列中具有良好的选择性指数（SI > 2）。分子模拟研究表明，设计的化合物能够与两个镁离子形成关键配位，并与HCV NS5B活性位点的其他关键残基相互作用。
