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

Aurones are a small subgroup of flavonoids in which thebasic C-6-C-3-C-6 skeletonis arrangedas (Z)-2-benzylidenebenzofuran-3(2H)-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 activityof a series of 25 aurones bearing different oxygenated groups (OH,OCH3, OCH2OCH3, OCH2O,OCF2H, and OCH2C6H4R)at the A- and/or B-rings using cell-based screening assays. We observedthat 12 of the 25 compounds exhibit EC50 < 3 mu M(8e, 8h, 8j, 8k, 8l, 8m, 8p, 8q, 8r, 8w, 8x, and 8y), of which five presented EC50 < 1 mu M (8h, 8m, 8p, 8q, and 8w) without evident cytotoxic effect in Calu-3 cells. Thesubstitution of the A- and/or B-ring with OCH3, OCH2OCH3, and OCF2H groups seems beneficialfor the antiviral activity, while the corresponding phenolic derivativesshowed a significant decrease in the anti-SARS-CoV-2 activity. Themost potent compound of the series, aurone 8q (EC50 = 0.4 mu M, SI = 2441.3), is 2 to 3 times more effectivethan the polyphenolic flavonoids myricetin (2) and baicalein(1), respectively. Investigation of the five more activecompounds as inhibitors of SARS-CoV-2 3CL(pro) based on moleculardynamic calculations suggested that these aurones should detach fromthe active site of 3CL(pro), and, probably, they could bindto another SARS-CoV-2 protein target (either receptor or enzyme).

Automated summary

In this study, a series of 25 aurone compounds with different oxygenated groups were designed, synthesized, and tested for their anti-SARS-CoV-2 activity. Twelve compounds exhibited significant activity with EC50 < 3 μM, and five compounds showed even higher activity with EC50 < 1 μM without cytotoxic effects. The most potent compound, aurone 8q, was 2 to 3 times more effective than the polyphenolic flavonoids myricetin and baicalein. Molecular dynamic calculations suggested that these aurones may bind to another SARS-CoV-2 protein target.