Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-09-05 DOI:10.1016/j.ejmech.2024.116832

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Abstract

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 EC₅₀ value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC₅₀ 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.

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丙型肝炎病毒 NS5B拇指部位 II 抑制剂中羧酸基团的生物异位取代：苯丙氨酸衍生物

丙型肝炎病毒（HCV）是全球关注的健康问题，由于其在病毒复制中的作用，HCV 的 NS5B RNA 依赖性 RNA 聚合酶（RdRp）是一个具有吸引力的药物发现靶点。本研究重点关注 NS5B拇指位点 II 抑制剂，特别是苯丙氨酸衍生物，并探索生物异构替代和原药策略，以克服与羧酸功能相关的限制。合成的化合物具有抗病毒活性，其中化合物 6d 的 EC50 值为 3.717 μM，活性最强。羟脒衍生物 7a-d 的 EC50 值从 3.9 μM 到 11.3 μM 不等。然而，含有噁二唑酮环（8a-d）和噁二唑硫酮环（9a-d）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 时显示出一丝活性。新戊酰氧基甲基衍生物 11a 和 11b 没有显示出抗病毒活性。为了充分了解这些修饰的效果，并探索开发新型 HCV 治疗方案的其他策略，我们有必要开展进一步的研究。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.