Synthesis and bioevaluation of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acids as potent xanthine oxidase inhibitors

• A series of new non-purine XO inhibitors were designed and synthesized.
• The selenium-containing heterocycle was first introduced into XO inhibitors.
• Inhibitory activity of compound 9e was 3-fold more potent than that of febuxostat.
• Steady-state kinetics data demonstrated that 9e was a mixed-type XO inhibitor.
• Molecular docking studies gained an insight into binding mode of 9e with XO.

A series of 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acid derivatives (8a–f, 9a–m) were synthesized and evaluated for inhibitory activity against xanthine oxidase in vitro. Structure–activity relationship analyses have also been presented. Most of the target compounds exhibited potency levels in the nanomolar range. Compound 9e emerged as the most potent xanthine oxidase inhibitor (IC50 = 5.5 nM) in comparison to febuxostat (IC50 = 18.6 nM). Steady-state kinetics measurements with the bovine milk enzyme indicated a mixed type inhibition with Ki and Ki′ values of 0.9 and 2.3 nM, respectively. A molecular modeling study on compounds 9e was performed to gain an insight into its binding mode with xanthine oxidase, and to provide the basis for further structure-guided design of new non-purine xanthine oxidase inhibitors related with 2-phenyl-4-methyl-1,3-selenazole-5-carboxylic acid scaffold.

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