Discovery of the first non-planar flavonoid that can strongly inhibit xanthine oxidase: protoapigenone 1′-O-propargyl ether

Xanthine oxidase (XO) is a key enzyme in purine metabolism with an important role in various pathologies. Several flavonoids have been reported for their capacity to inhibit this enzyme, and, for these compounds, the ability to adopt a planar 3D structure has been accepted as fundamental prerequisite for such activity. Here we report the in vitro investigation of a series of non-planar protoflavone derivatives as XO inhibitors, among which protoapigenone 1′-O-propargyl ether was found to be an efficient competitive inhibitor of the enzyme with an IC50 value of 3.61 μM, significantly (p <0.001) stronger than the anti-gout drug allopurinol (IC50 = 8.72 μM). Methoxy substitution at C-7, however, resulted in complete loss of activity. In silico docking supported the observed structure–activity relationships, based on which a ‘planar structure’ itself can no longer be considered as a criterion for flavonoid-type inhibitors of XO.