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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 \u03bcM 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 \u00b1 0.05 and 0.37 \u00b1 0.05 \u00b5M, 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.<\/jats:p>","DOI":"10.3390\/v16111768","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T06:10:48Z","timestamp":1731478248000},"page":"1768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8747-8976","authenticated-orcid":false,"given":"Luana G.","family":"de Souza","sequence":"first","affiliation":[{"name":"Instituto de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, Ilha do Fund\u00e3o, CCS, Bloco H\u2014Sala H29, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduarda A.","family":"Penna","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Modelagem Computacional, Grupo de Modelagem Computacional Aplicada, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1350-1301","authenticated-orcid":false,"given":"Alice S.","family":"Rosa","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Morfologia e Morfog\u00eanese Viral, Instituto Oswaldo Cruz, Rio de Janeiro 21041-250, RJ, Brazil"},{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Biologia Celular e Molecular, Instituto Oswaldo Cruz, Rio de Janeiro 21041-250, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana C.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, Ilha do Fund\u00e3o, CCS, Bloco H\u2014Sala H29, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Schaeffer","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, Ilha do Fund\u00e3o, CCS, Bloco H\u2014Sala H29, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana V.","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, Ilha do Fund\u00e3o, CCS, Bloco H\u2014Sala H29, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2599-4633","authenticated-orcid":false,"given":"Dennis M.","family":"de Paiva","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa de Produtos Naturais, Universidade Federal do Rio de Janeiro, Ilha do Fund\u00e3o, CCS, Bloco H\u2014Sala H29, Rio de Janeiro 21941-902, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8075-3253","authenticated-orcid":false,"given":"Vinicius C.","family":"de Souza","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Modelagem Computacional, Grupo de Modelagem Computacional Aplicada, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian Neuza S.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Morfologia e Morfog\u00eanese Viral, Instituto Oswaldo Cruz, Rio de Janeiro 21041-250, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6137-8272","authenticated-orcid":false,"given":"Daniel D. 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