Carboxylated chalcones and related flavonoids as inhibitors of xanthine oxidase

Carboxylated chalcones and other related flavonoids were synthesized and evaluated as inhibitors of xanthine oxidase, which is a known target for synthetic and herbal drugs used against hyperuricemia, gout, and other diseases. The 4-carboxylated chalcones with hydroxy, methoxy, and ethoxy groups at ring A were found to exhibit in vitro inhibitory activities with IC 50 values in the range of 0.057 to 0.26 μM, being 10–60-fold more potent than allopurinol. Structurally related carboxylic acids with Δ 3,9 -homoisoflavonoid and flavone scaffolds also showed micromolar activity towards xanthine oxidase. At the same time, dihydrochalcone and Δ 2,3 -homoisoflavonoid carboxylic acids as well as their oxa -analogues were more than two orders of magnitude less effective inhibitors. Kinetic and molecular docking studies indicated that the carboxylated chalcones and Δ 3,9 -homoisoflavonoids are mixed-type inhibitors, which mostly bind to free enzyme occupying the active site of xanthine oxidase. Graphical Abstract