Pyrazolo[3,4-d]pyrimidine-based neplanocin analogues identified as potential de novo pharmacophores for dual-target HBV inhibition†

IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics
MedChemComm Pub Date : 2025-02-20 DOI:10.1039/D4MD00932K
Mohan Kasula, Masaaki Toyama, Ramakrishnamraju Samunuri, Ashok Kumar Jha, Mika Okamoto, Masanori Baba and Ashoke Sharon
{"title":"Pyrazolo[3,4-d]pyrimidine-based neplanocin analogues identified as potential de novo pharmacophores for dual-target HBV inhibition†","authors":"Mohan Kasula, Masaaki Toyama, Ramakrishnamraju Samunuri, Ashok Kumar Jha, Mika Okamoto, Masanori Baba and Ashoke Sharon","doi":"10.1039/D4MD00932K","DOIUrl":null,"url":null,"abstract":"<p >The discovery of selective and potent inhibitors through <em>de novo</em> pathways is essential to combat drug resistance in chronic hepatitis B (CHB) infections. Recent studies have highlighted that neplanocin A (NepA) derivatives are biologically selective inhibitors of the hepatitis B virus (HBV). In this study, we designed, synthesized, and evaluated various pyrazolo[3,4-<em>d</em>]pyrimidine-based NepA analogues (<strong>4a–h</strong>) for their anti-HBV activity. Notably, analogue <strong>4g</strong> demonstrated significant activity against HBV replication, with EC<small><sub>50</sub></small> (HBV DNA) = 0.96 μM, CC<small><sub>50</sub></small> &gt; 100 μM and EC<small><sub>50</sub></small> (HBsAg) = 0.82 μM, showing selective inhibition of HBsAg secretion. The SAR analysis concluded that replacing the polar 4-NH<small><sub>2</sub></small> group with –CH<small><sub>3</sub></small> also acted as a weak H-bonding donor, and the presence of 3-iodo was found to be desirable for the activity/toxicity profile. The nucleoside analogues exhibited a distinct mechanism of action compared to existing nucleoside analogues for the selective inhibition of HBsAg secretion. Based on these findings, compound <strong>4g</strong> represents a promising lead molecule for the development of new anti-HBV agents with unique mechanisms of action.</p>","PeriodicalId":88,"journal":{"name":"MedChemComm","volume":" 4","pages":" 1740-1745"},"PeriodicalIF":3.5970,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"MedChemComm","FirstCategoryId":"1085","ListUrlMain":"https://pubs.rsc.org/en/content/articlelanding/2025/md/d4md00932k","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
引用次数: 0

Abstract

The discovery of selective and potent inhibitors through de novo pathways is essential to combat drug resistance in chronic hepatitis B (CHB) infections. Recent studies have highlighted that neplanocin A (NepA) derivatives are biologically selective inhibitors of the hepatitis B virus (HBV). In this study, we designed, synthesized, and evaluated various pyrazolo[3,4-d]pyrimidine-based NepA analogues (4a–h) for their anti-HBV activity. Notably, analogue 4g demonstrated significant activity against HBV replication, with EC50 (HBV DNA) = 0.96 μM, CC50 > 100 μM and EC50 (HBsAg) = 0.82 μM, showing selective inhibition of HBsAg secretion. The SAR analysis concluded that replacing the polar 4-NH2 group with –CH3 also acted as a weak H-bonding donor, and the presence of 3-iodo was found to be desirable for the activity/toxicity profile. The nucleoside analogues exhibited a distinct mechanism of action compared to existing nucleoside analogues for the selective inhibition of HBsAg secretion. Based on these findings, compound 4g represents a promising lead molecule for the development of new anti-HBV agents with unique mechanisms of action.

吡唑罗[3,4-d]嘧啶基新行星素类似物被鉴定为双靶点抑制HBV的潜在新药物载体。
通过新生途径发现选择性和有效的抑制剂对于对抗慢性乙型肝炎(CHB)感染的耐药性至关重要。最近的研究强调,neplanocin A (NepA)衍生物是乙型肝炎病毒(HBV)的生物选择性抑制剂。在本研究中,我们设计、合成并评价了各种吡唑[3,4-d]嘧啶基NepA类似物(4a-h)的抗hbv活性。值得注意的是,类似物4g显示出明显的抑制HBV复制的活性,EC50 (HBV DNA) = 0.96 μM, CC50 (bbb100 μM)和EC50 (HBsAg) = 0.82 μM,显示出选择性抑制HBsAg分泌。SAR分析得出结论,用-CH3取代极性的4-NH2基团也可以作为弱h键供体,并且发现3-碘的存在对于活性/毒性谱是理想的。与现有的核苷类似物相比,核苷类似物在选择性抑制HBsAg分泌方面表现出独特的作用机制。基于这些发现,化合物4g代表了开发具有独特作用机制的新型抗hbv药物的有希望的先导分子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
MedChemComm
MedChemComm BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
4.70
自引率
0.00%
发文量
0
审稿时长
2.2 months
期刊介绍: Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry. In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信