Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights
Luana G. de Souza, Eduarda Alves Penna, Alice dos Santos Rosa, Juliana C. da Silva, Edgar Schaeffer, Juliana V. Guimarães, Dennis M. de Paiva, Vinícius Carius de Souza, Vivian Neuza S. Ferreira, Daniel Dias Coutinho de Souza, Sylvia Roxo, Giovanna Barbosa da Conceição, Larissa Esteves Carvalho Constant, Giovanna B. Frenzel, Matheus José Novais Landim, Maria Luiza Pereira Baltazar, Celimar Sinézia, Ana Laura Macedo Brand, José Ronaldo Souza Nunes, Tadeu Lima Montagnoli · Viruses · 2024
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.