Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships exploration.

The main protease (M) represents one of the most effective and attractive targets for designing anti-SARS-CoV-2 drugs. In this study, we designed and synthesized a novel series of Ebselen derivatives by incorporating privileged fragments from different pockets of the M active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 M inhibition assay, with IC values ranging from 233 nM to 550 nM. Notably, compound 3a displayed submicromolar M activity (IC = 364 nM) and low micromolar antiviral activity (EC = 8.01 µM), comparable to that of Ebselen (IC = 339 nM, EC = 3.78 µM). Time-dependent inhibition assay confirmed that these compounds acted as covalent inhibitors. Taken together, our optimization campaigns thoroughly explored the structural diversity of Ebselen and verified the impact of specific modifications on potency against M.