Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116, Istanbul, Turkey; Graduate School of Health Sciences, Istanbul University, 34126, Istanbul, Turkey.
Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34093, Istanbul, Turkey.
Eur J Med Chem. 2024 Dec 5;279:116832. doi: 10.1016/j.ejmech.2024.116832. Epub 2024 Sep 5.
Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.
丙型肝炎病毒 (HCV) 是一个全球性的健康问题，HCV 的 NS5B RNA 依赖性 RNA 聚合酶 (RdRp) 是药物发现的一个有吸引力的靶点，因为它在病毒复制中起作用。本研究集中在 NS5B 拇指位点 II 抑制剂上，特别是苯丙氨酸衍生物，并探索生物等排替代和前药策略，以克服与羧酸功能相关的限制。合成的化合物表现出抗病毒活性，化合物 6d 的 EC 值为 3.717 μM，显示出最强的活性。羟脒衍生物 7a-d 的 EC 值范围为 3.9 μM 至 11.3 μM。然而，含有噁二唑酮 (8a-d) 和噁二唑硫酮 (9a-d) 环的酸性杂环衍生物没有表现出可测量的活性。甲基化杂环 10b 在 8.09 μM 时显示出一定的活性。戊酰氧甲基衍生物 11a 和 11b 没有表现出抗病毒活性。需要进一步的研究来充分了解这些修饰的影响，并探索开发 HCV 新型治疗选择的其他策略。
