Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication.

Aurones are a small subgroup of flavonoids in which the basic C-C-C skeleton is arranged as ()-2-benzylidenebenzofuran-3(2)-one. These compounds are structural isomers of flavones and flavonols, natural products reported as potent inhibitors of SARS-CoV-2 replication. Herein, we report the design, synthesis, and anti-SARS-CoV-2 activity of a series of 25 aurones bearing different oxygenated groups (OH, OCH, OCHOCH, OCHO, OCFH, and OCHCHR) at the A- and/or B-rings using cell-based screening assays. We observed that 12 of the 25 compounds exhibit EC < 3 μM (, , , , , , , , , , , and ), of which five presented EC < 1 μM (, , , , and ) without evident cytotoxic effect in Calu-3 cells. The substitution of the A- and/or B-ring with OCH, OCHOCH, and OCFH groups seems beneficial for the antiviral activity, while the corresponding phenolic derivatives showed a significant decrease in the anti-SARS-CoV-2 activity. The most potent compound of the series, aurone (EC = 0.4 μM, SI = 2441.3), is 2 to 3 times more effective than the polyphenolic flavonoids myricetin () and baicalein (), respectively. Investigation of the five more active compounds as inhibitors of SARS-CoV-2 3CL based on molecular dynamic calculations suggested that these aurones should detach from the active site of 3CL, and, probably, they could bind to another SARS-CoV-2 protein target (either receptor or enzyme).