Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication
Guilherme S. Caleffi, Alice dos Santos Rosa, Luana G. de Souza, João L. S. Avelar, Sarah M. R. Nascimento, Vitor Martins de Almeida, Amanda Resende Tucci, Vivian Neuza S. Ferreira, Alcides J. M. da Silva, Osvaldo A. Santos‐Filho, Milene Dias Miranda, Paulo R. R. Costa
Abstract
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).