Journal Article

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

Rosa, Alice S., Baltazar, Maria Luiza P., Nunes, Julia Santos, de Souza, Luana G., Ferreira, Vivian Neuza S., Montagnoli, Tadeu L., Souza, Daniel D. C., Roxo, Sylvia, Penna, Eduarda A., Schaeffer, Edgar, da Silva, Juliana C., Brand, Ana Laura Macedo, Conceição, Giovanna B., Miranda, Milene D., Guimarães, Juliana V., de Paiva, Dennis M., Allonso, Diego, Alves, Marina Amaral, Zapata-Sudo, Gisele, Goliatt, Priscila V. Z. Capriles, de Souza, Vinicius C., Constant, Larissa E. C., Silva, Celimar Cinézia, da Silva, Alcides J. M., Frenzel, Giovanna B., Landim, Matheus J. N.

2024

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Animals / Antiviral agents / Antiviral Agents - chemical synthesis / Antiviral Agents - chemistry / Antiviral Agents - pharmacokinetics / Antiviral Agents - pharmacology / Antiviral drugs / Bioavailability / Cell Line / Chlorocebus aethiops / Chromatography / Comparative analysis / Coronavirus 3C Proteases - antagonists & inhibitors / Coronavirus 3C Proteases - chemistry / Coronavirus 3C Proteases - metabolism / Coronavirus Papain-Like Proteases - antagonists & inhibitors / Coronavirus Papain-Like Proteases - chemistry / Coronavirus Papain-Like Proteases - metabolism / COVID-19 / COVID-19 - virology / COVID-19 Drug Treatment / Cytotoxicity / Design and construction / Enzymes / Fourier transforms / Humans / in vitro assays / Influenza / main protease (Mpro) / Models, Molecular / molecular docking / Molecular Docking Simulation / Molecular modelling / Molecules / Morbidity / Natural products / Pandemics / Papain / papain-like protease (PLpro) / Pharmacokinetics / Physiological aspects / protease inhibition / Protease Inhibitors - chemical synthesis / Protease Inhibitors - chemistry / Protease Inhibitors - pharmacokinetics / Protease Inhibitors - pharmacology / Public health / SARS-CoV-2 - drug effects / SARS-CoV-2 inhibition / Severe acute respiratory syndrome coronavirus 2 / Virus Replication - drug effects / Viruses