作为 SARS-CoV-2 复制抑制剂的苯并咔唑内酯:合成、细胞研究、酶抑制、分子建模和药代动力学洞察。

IF 3.8 3区 医学 Q2 VIROLOGY
Viruses-Basel Pub Date : 2024-11-13 DOI:10.3390/v16111768
Luana G de Souza, Eduarda A Penna, Alice S Rosa, Juliana C da Silva, Edgar Schaeffer, Juliana V Guimarães, Dennis M de Paiva, Vinicius C de Souza, Vivian Neuza S Ferreira, Daniel D C Souza, Sylvia Roxo, Giovanna B Conceição, Larissa E C Constant, Giovanna B Frenzel, Matheus J N Landim, Maria Luiza P Baltazar, Celimar Cinézia Silva, Ana Laura Macedo Brand, Julia Santos Nunes, Tadeu L Montagnoli, Gisele Zapata-Sudo, Marina Amaral Alves, Diego Allonso, Priscila V Z Capriles Goliatt, Milene D Miranda, Alcides J M da Silva
{"title":"作为 SARS-CoV-2 复制抑制剂的苯并咔唑内酯:合成、细胞研究、酶抑制、分子建模和药代动力学洞察。","authors":"Luana G de Souza, Eduarda A Penna, Alice S Rosa, Juliana C da Silva, Edgar Schaeffer, Juliana V Guimarães, Dennis M de Paiva, Vinicius C de Souza, Vivian Neuza S Ferreira, Daniel D C Souza, Sylvia Roxo, Giovanna B Conceição, Larissa E C Constant, Giovanna B Frenzel, Matheus J N Landim, Maria Luiza P Baltazar, Celimar Cinézia Silva, Ana Laura Macedo Brand, Julia Santos Nunes, Tadeu L Montagnoli, Gisele Zapata-Sudo, Marina Amaral Alves, Diego Allonso, Priscila V Z Capriles Goliatt, Milene D Miranda, Alcides J M da Silva","doi":"10.3390/v16111768","DOIUrl":null,"url":null,"abstract":"<p><p>Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (<b>4a</b>, <b>4b</b>, <b>4d</b>, and <b>4i</b>) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds <b>4a</b> and <b>4b</b> showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound <b>4a</b> was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.</p>","PeriodicalId":49328,"journal":{"name":"Viruses-Basel","volume":"16 11","pages":""},"PeriodicalIF":3.8000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11598835/pdf/","citationCount":"0","resultStr":"{\"title\":\"Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights.\",\"authors\":\"Luana G de Souza, Eduarda A Penna, Alice S Rosa, Juliana C da Silva, Edgar Schaeffer, Juliana V Guimarães, Dennis M de Paiva, Vinicius C de Souza, Vivian Neuza S Ferreira, Daniel D C Souza, Sylvia Roxo, Giovanna B Conceição, Larissa E C Constant, Giovanna B Frenzel, Matheus J N Landim, Maria Luiza P Baltazar, Celimar Cinézia Silva, Ana Laura Macedo Brand, Julia Santos Nunes, Tadeu L Montagnoli, Gisele Zapata-Sudo, Marina Amaral Alves, Diego Allonso, Priscila V Z Capriles Goliatt, Milene D Miranda, Alcides J M da Silva\",\"doi\":\"10.3390/v16111768\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (<b>4a</b>, <b>4b</b>, <b>4d</b>, and <b>4i</b>) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds <b>4a</b> and <b>4b</b> showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound <b>4a</b> was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.</p>\",\"PeriodicalId\":49328,\"journal\":{\"name\":\"Viruses-Basel\",\"volume\":\"16 11\",\"pages\":\"\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2024-11-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11598835/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Viruses-Basel\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3390/v16111768\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"VIROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Viruses-Basel","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/v16111768","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"VIROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

地方性和大流行性病毒是公共卫生的重大挑战,长期以来会导致大量的发病率和死亡率。COVID-19 大流行凸显了开发和发现新型强效抗病毒药物的迫切需要。在本研究中,我们介绍了一系列苯并咔唑内酯类化合物的合成和抗 SARS-CoV-2 活性,并利用基于细胞的筛选试验对其进行了评估。结果表明,4 个化合物(4a、4b、4d 和 4i)在 Calu-3 细胞中的 EC50 值低于 4 μM,且无细胞毒性作用。对抑制 SARS-CoV-2 主要蛋白酶(Mpro)和木瓜蛋白酶(PLpro)的机理研究采用了酶学测定法。值得注意的是,化合物 4a 和 4b 具有抑制 Mpro 的活性,其 IC50 值分别为 0.11 ± 0.05 和 0.37 ± 0.05 µM。此外,研究人员还进行了分子对接、理化和药代动力学研究,以验证其机理并评估其生物利用度。化合物 4a 被选中进行初步的药物相似性分析和体内药代动力学研究,结果很好,证实了体外和硅学研究结果,增强了其作为抗 SARS-CoV-2 先导化合物的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights.

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Viruses-Basel
Viruses-Basel VIROLOGY-
CiteScore
7.30
自引率
12.80%
发文量
2445
审稿时长
1 months
期刊介绍: Viruses (ISSN 1999-4915) is an open access journal which provides an advanced forum for studies of viruses. It publishes reviews, regular research papers, communications, conference reports and short notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. We also encourage the publication of timely reviews and commentaries on topics of interest to the virology community and feature highlights from the virology literature in the ''News and Views'' section. Electronic files or software regarding the full details of the calculation and experimental procedure, if unable to be published in a normal way, can be deposited as supplementary material.
×
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