Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Farmaceutica II, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
J Med Chem. 2013 Mar 28;56(6):2270-82. doi: 10.1021/jm301643a. Epub 2013 Mar 7.
The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure-based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the meta-fluoro-N-1-phenyl pyrazolobenzothiazine derivative 4a, which exhibited an EC50 = 3.6 μM, EC90 = 25.6 μM, and CC50 > 180 μM in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution.
NS5B RNA 依赖性 RNA 聚合酶是开发新型和选择性丙型肝炎病毒复制抑制剂的有吸引力的靶标。为了鉴定新型结构命中物作为抗 HCV 药物，我们对内部文库进行了基于结构的虚拟筛选，然后进行了合理的药物设计、有机合成和生物测试。这些研究确定了吡唑并苯并噻嗪骨架作为获得针对 NS5B 聚合酶的新型抗 HCV 药物的合适模板。该系列中最好的化合物是间氟-N-1-苯基吡唑并苯并噻嗪衍生物 4a，其在 Huh 9-13 复制子系统中的 EC50 = 3.6 μM，EC90 = 25.6 μM，CC50 > 180 μM，因此为进一步的命中进化提供了一个良好的起点。
