A rational approach to the design of flavones as xanthine oxidase inhibitors

In the light of previous QSAR studies on flavones as inhibitors of xanthine oxidase, we synthesized and tested a new series of 7-hydroxyflavones carrying a wide and balanced variety of substituents (pi, sigma(p)) at the 4' position in order to explore the effect of substituents at this position on the xanthine oxidase inhibitory activity. The results of pK(a) determinations show that the electronic effects of the substituents are not transferred to the hydroxyl at C7, previously found to be fundamental for activity. An excellent correlation is found between molar refractivity of the substituents and the inhibitory activity. These results, applied to the more active 5,7-dihydroxyflavones, allowed the design and synthesis of a very active inhibitor, with an IC50 in the nanomolar range. On interpretative grounds, C4' substituents of flavones are involved in dispersion interactions with the enzyme. The calculation of quantum chemical polarizabilities and solvent accessible surface areas suggests the existence of pi-pi stacking interactions with an aromatic aminoacidic residue of the enzyme.