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

Traditional herbal medicine offers opportunities to discover novel therapeutics against SARS-CoV-2 mutation. The dried aerial part of mint ( L.) was chosen for bioactivity-guided extraction. Seven constituents were isolated and characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Syringic acid and methyl rosmarinate were evaluated in drug combination treatment. Ten amide derivatives of methyl rosmarinate were synthesized, and the dodecyl () and 3-ethylphenyl () derivatives demonstrated significant improvement in the anti-SARS-CoV-2 plaque reduction assay, achieving IC of 0.77 and 2.70 μM, respectively, against Omicron BA.1 as compared to methyl rosmarinate's IC of 57.0 μM. Spike protein binding and 3CL inhibition assays were performed to explore the viral inhibition mechanism. Molecular docking of compounds and to 3CL was performed to reveal potential interaction. In summary, natural products with anti-Omicron BA.1 activity were isolated from and derivatives of methyl rosmarinate were synthesized, showing 21- to 74-fold improvement in antiviral activity against Omicron BA.1.