Dipartimento di Chimica e Tecnologia del Farmaco, University of Perugia, 06123 Perugia, Italy.
Bioorg Med Chem. 2012 Jan 15;20(2):866-76. doi: 10.1016/j.bmc.2011.11.061. Epub 2011 Dec 3.
Hepatitis C virus (HCV) infection has been recognized as the major cause of liver failure that can lead to hepatocellular carcinoma. Among all the HCV proteins, NS5B polymerase represents a leading target for drug discovery strategies. Herein, we describe our initial research efforts towards the identification of new chemotypes as allosteric NS5B inhibitors. In particular, the design, synthesis, in vitro anti-NS5B and in cellulo anti-HCV evaluation of a series of 1-oxo-1H-pyrido[2,1-b][1,3]benzothiazole-4-carboxylate derivatives are reported. Some of the newly synthesized compounds showed an IC(50) ranging from 11 to 23 μM, and molecular modeling and biochemical studies suggested that the thumb domain could be the target site for this new class of NS5B inhibitors.
丙型肝炎病毒 (HCV) 感染已被认为是导致肝衰竭的主要原因，而肝衰竭可能进一步导致肝细胞癌。在所有 HCV 蛋白中，NS5B 聚合酶是药物发现策略的主要靶标。本文描述了我们在鉴定新型变构 NS5B 抑制剂的化学型方面的初步研究成果。特别是，报告了一系列 1-氧代-1H-吡啶并[2,1-b][1,3]苯并噻唑-4-羧酸酯衍生物的设计、合成、体外抗 NS5B 和细胞内抗 HCV 评价。一些新合成的化合物的 IC50 范围为 11 至 23 μM，分子建模和生化研究表明，拇指结构域可能是该新型 NS5B 抑制剂的靶标部位。
