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 (<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.
Authors
- Tadeu L. Montagnoli (ORCID: https://orcid.org/0000-0003-1196-0149)
- José Ronaldo Souza Nunes (ORCID: https://orcid.org/0000-0001-5668-3646)
- Vivian Neuza S. Ferreira
- Larissa Esteves Carvalho Constant (ORCID: https://orcid.org/0000-0003-4011-8532)
- Priscila Vanessa Zabala Capriles Goliatt (ORCID: https://orcid.org/0000-0001-9780-4328)
- Milene Dias Miranda (ORCID: https://orcid.org/0000-0003-0037-059X)
- Celimar Sinézia (ORCID: https://orcid.org/0000-0001-5992-2307)
- Alcides J. M. da Silva (ORCID: https://orcid.org/0000-0002-3200-0318)
- Daniel Dias Coutinho de Souza
- Juliana Bohnen Guimarães (ORCID: https://orcid.org/0000-0003-4142-8591)
- Alice dos Santos Rosa (ORCID: https://orcid.org/0000-0002-1350-1301)
- Matheus José Novais Landim (ORCID: https://orcid.org/0009-0003-7824-4232)
- Eduarda Alves Penna (ORCID: https://orcid.org/0000-0003-2374-6924)
- Diego Allonso (ORCID: https://orcid.org/0000-0002-1410-480X)
- Ana Laura Macedo Brand (ORCID: https://orcid.org/0009-0003-4963-6376)
- Luana G. de Souza (ORCID: https://orcid.org/0000-0002-8747-8976)
- Juliana C. da Silva
- Marina Amaral Alves (ORCID: https://orcid.org/0000-0002-8188-5554)
- Edgar Schaeffer (ORCID: https://orcid.org/0000-0002-5262-6983)
- Vinícius Carius de Souza (ORCID: https://orcid.org/0000-0001-8075-3253)
- Sylvia Roxo
- Gisele Zapata-Sudo
- Maria Luiza Pereira Baltazar
- Giovanna Barbosa da Conceição (ORCID: https://orcid.org/0009-0000-4098-9886)
- Giovanna B. Frenzel
- Dennis M. de Paiva
Institutions
- Universidade Federal de Juiz de Fora (BR)
- Universidade Federal do Rio de Janeiro (BR)
- Fundação Oswaldo Cruz (BR)
Publication Details
- Journal
- Viruses
- Published
- 2024-11-13
- DOI
- https://doi.org/10.3390/v16111768
- Citations
- 1
- Primary Topic
- Computational Drug Discovery Methods
- Type
- article
- Field-Weighted Citation Impact
- 0.36
Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
- Universidade Federal do Rio de Janeiro