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

A series of Ebselen derivatives with improve activity and selectivity were discovered by introducing privilege groups that reported to be preferred by SARS-CoV-2 Mpro active site. [Display omitted] • We discover 24 novel Ebselen derivatives as SARS-CoV-2 Mpro inhibitors. • 3a inhibits SARS-CoV-2 replication in Vero-E6 cells with low micromolar activity. • Novel Ebselen derivatives are covalent SARS-CoV-2 Mpro inhibitors. • 10f selectively inhibits Mpro without inhibiting human cysteine proteases cathepsin B and cathepsin K. The main protease (Mpro) 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 Mpro active site. Among these compounds, 11 compounds showed submicromolar activity in the FRET-based SARS-CoV-2 Mpro inhibition assay, with IC 50 values ranging from 233 nM to 550 nM. Notably, compound 3a displayed submicromolar Mpro activity (IC 50 = 364 nM) and low micromolar antiviral activity (EC 50 = 8.01 µM), comparable to that of Ebselen (IC 50 = 339 nM, EC 50 = 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 Mpro. [ABSTRACT FROM AUTHOR]