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.

A strategy for the selective C-H alkenylation of flavones is described. By using the carbonyl group of the flavone core as an intrinsic directing group, a series of 5-alkenylated derivatives were synthesized via coupling with alkenes, including acrylates, styrene, methyl vinyl ketone, and phenyl vinyl sulfone, affording the desired products in good to excellent yields (up to 92%). Notably, when a carbamate substituent was present at C7, the reaction proceeded with complete chemoselectivity, exclusively yielding C-5 alkenylated products. Although carbamate groups are widely recognized as efficient directing groups in alkenylation reactions, they proved to be ineffective within the flavone scaffold. Density functional theory (DFT) calculations were performed to rationalize the observed chemoselectivity and to provide mechanistic insight into the C-H activation process. The preference for C5 alkenylation arises from the lower energy profiles of the corresponding transition states and intermediates, whereas C8 functionalization is disfavored due to a greater tendency toward protodemetalation over migratory insertion.