Biflavonoids from Torreya nucifera displaying SARS-CoV 3CLpro inhibition

As part of our search for botanical sources of SARS-CoV 3CLpro inhibitors, we selected Torreya nucifera, which is traditionally used as a medicinal plant in Asia. The ethanol extract of T. nucifera leaves exhibited good SARS-CoV 3CLpro inhibitory activity (62% at 100 μg/mL). Following bioactivity-guided fractionation, eight diterpenoids (1–8) and four biflavonoids (9–12) were isolated and evaluated for SARS-CoV 3CLpro inhibition using fluorescence resonance energy transfer analysis. Of these compounds, the biflavone amentoflavone (9) (IC50 = 8.3 μM) showed most potent 3CLpro inhibitory effect. Three additional authentic flavones (apigenin, luteolin and quercetin) were tested to establish the basic structure–activity relationship of biflavones. Apigenin, luteolin, and quercetin inhibited 3CLpro activity with IC50 values of 280.8, 20.2, and 23.8 μM, respectively. Values of binding energy obtained in a molecular docking study supported the results of enzymatic assays. More potent activity appeared to be associated with the presence of an apigenin moiety at position C-3′ of flavones, as biflavone had an effect on 3CLpro inhibitory activity.

Inhibitory activity appeared to be associated with the presence of an apigenin moiety at position C-3′ of flavones, as biflavonoid had an effect on SARS-CoV 3CLpro inhibitory activity.Figure optionsDownload as PowerPoint slide