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

Aurones are a small subgroup of flavonoids in which the basic C 6 -C 3 -C 6 skeleton is arranged as ( Z )-2-benzylidenebenzofuran-3(2 H )-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 3 , OCH 2 OCH 3 , OCH 2 O, OCF 2 H, and OCH 2 C 6 H 4 R) at the A- and/or B-rings using cell-based screening assays. We observed that 12 of the 25 compounds exhibit EC 50 < 3 μM ( 8e , 8h , 8j , 8k , 8l , 8m , 8p , 8q , 8r , 8w , 8x , and 8y ), of which five presented EC 50 < 1 μM ( 8h , 8m , 8p , 8q , and 8w ) without evident cytotoxic effect in Calu-3 cells. The substitution of the A- and/or B-ring with OCH 3 , OCH 2 OCH 3 , and OCF 2 H 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 8q (EC 50 = 0.4 μM, SI = 2441.3), is 2 to 3 times more effective than the polyphenolic flavonoids myricetin ( 2 ) and baicalein ( 1 ), respectively. Investigation of the five more active compounds as inhibitors of SARS-CoV-2 3CL pro based on molecular dynamic calculations suggested that these aurones should detach from the active site of 3CL pro , and, probably, they could bind to another SARS-CoV-2 protein target (either receptor or enzyme).