Recruitment of chalcone's potential in drug discovery of anti-SARS-CoV-2 agents

Chalcone is an interesting scaffold found in the structure of many naturally occurring molecules. Medicinal chemists are commonly interested in designing new chalcone-based structures because of having the alpha, beta-unsaturated ketone functional group, which allows these compounds to participate in Michael's reaction and create strong covalent bonds at the active sites of the targets. Some studies have identified several natural chalcone-based compounds with the ability to inhibit the severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus proteases. A few years after the advent of the coronavirus disease 2019 pandemic and the publication of many findings in this regard, there is some evidence that suggests chalcone scaffolding has great potential for use in the design and development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibitors. Artificial placement of this scaffold in the structure of optimized anti-SARS-CoV-2 compounds can potentially provide irreversible inhibition of the viral cysteine proteases 3-chymotrypsin-like protease and papain-like protease by creating Michael interaction. Despite having remarkable capabilities, the use of chalcone scaffold in drug design and discovery of SARS-CoV-2 inhibitors seems to have been largely neglected. This review addresses issues that could lead to further consideration of chalcone scaffolding in the structure of SARS-CoV-2 protease inhibitors in the future.