Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights

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Abstract
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.
Funding Information
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Fundação Oswaldo Cruz (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Fundação Oswaldo Cruz (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (E-26/201.426/2022, E-26/203.183/2023, E-26/260.041/2024, E-26/203.628/2024, 8888.506711/2020-01, 88887.694990/2022-00, IOC-023-FIO-18-2-58, VPPIS-004-FIO-22-2-21, 312027/2022-2)

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