Isolation of Anti-SARS-CoV-2 Natural Products Extracted from Mentha canadensis and the Semi-synthesis of Antiviral Derivatives

Traditionalherbal medicine offers opportunities to discover noveltherapeutics against SARS-CoV-2 mutation. The dried aerial part ofmint (Mentha canadensis L.) was chosenfor bioactivity-guided extraction. Seven constituents were isolatedand characterized by nuclear magnetic resonance (NMR) and mass spectrometry(MS). Syringic acid and methyl rosmarinate were evaluated in drugcombination treatment. Ten amide derivatives of methyl rosmarinatewere synthesized, and the dodecyl (13) and 3-ethylphenyl(19) derivatives demonstrated significant improvementin the anti-SARS-CoV-2 plaque reduction assay, achieving IC50 of 0.77 and 2.70 mu M, respectively, against Omicron BA.1 ascompared to methyl rosmarinate's IC50 of 57.0 mu M.Spike protein binding and 3CL(pro) inhibition assays wereperformed to explore the viral inhibition mechanism. Molecular dockingof compounds 13 and 19 to 3CL(pro) was performed to reveal potential interaction. In summary, naturalproducts with anti-Omicron BA.1 activity were isolated from Mentha canadensis and derivatives of methyl rosmarinatewere synthesized, showing 21- to 74-fold improvement in antiviralactivity against Omicron BA.1.