Xanthine oxidase (XO) is a molybdoflavoprotein that converts hypoxanthine to xanthine, which further generates uric acid within the human body. The potential increase in serum uric acid level (hyperuricemia) leads to deposition of sodium urate crystals in joints which results in inflammation and pain in joints. In this regard, xanthine oxidase is a selective target for sustaining broad-spectrum chemotherapy in hyperuricemic patients. Keeping in view the various biological attributes of flavones, two series of benzoflavone derivatives were rationally designed, synthesized and evaluated for their xanthine oxidase inhibitory potential. From both the series, eight compounds (NF-2, NF-4, NF-9, NF-12, NF-16, NF-25, NF-28, and NF-32) were found to exert significant XO inhibition with the IC50 values lower than 10 µM. Enzyme kinetic studies revealed that the most potent benzoflavone derivatives (NF-4 and NF-28) are mixed type inhibitors. Docking studies were also performed to investigate the binding interactions of potent molecules with the amino acid residues present in the active site of the enzyme, which confirmed that their favorable binding conformations in the active site of XO can completely block the catalytic activity of the enzyme. Benzoflavone derivatives exhibiting potent enzyme inhibition also showed promising results in hyperuricemic mice model, when tested in vivo.

Benzoflavone derivatives as potent antihyperuricemic agents

2019 Spring National Meeting

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