{"title":"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","authors":"","doi":"10.1016/j.ejmech.2024.116832","DOIUrl":null,"url":null,"abstract":"<div><p>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 <strong>6d</strong> showing the most potent activity with an EC<sub>50</sub> value of 3.717 μM. The hydroxamidine derivatives <strong>7a-d</strong> showed EC<sub>50</sub> values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (<strong>8a-d</strong>) and oxadiazolethione (<strong>9a-d</strong>) rings did not exhibit measurable activity. A methylated heterocycle <strong>10b</strong> showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives <strong>11a</strong> and <strong>11b</strong> 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.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.0000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives\",\"authors\":\"\",\"doi\":\"10.1016/j.ejmech.2024.116832\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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 <strong>6d</strong> showing the most potent activity with an EC<sub>50</sub> value of 3.717 μM. The hydroxamidine derivatives <strong>7a-d</strong> showed EC<sub>50</sub> values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (<strong>8a-d</strong>) and oxadiazolethione (<strong>9a-d</strong>) rings did not exhibit measurable activity. A methylated heterocycle <strong>10b</strong> showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives <strong>11a</strong> and <strong>11b</strong> 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.</p></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.0000,\"publicationDate\":\"2024-09-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S022352342400713X\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S022352342400713X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives
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.
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.
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