Xanthine oxidase (XO) is an enzyme that contains molybdenum at the active site and catalyzes the oxidation of purine bases to uric acid. Even though XO inhibitors are widely used for the treatment of hyperuricemia and gout, only very few such compounds are clinically used as drugs for the treatment of these diseases. Given the unique physicochemical properties of tropolone, i.e., its chelating effect and the pKa value that is similar to that of carboxylic acid, we have synthesized 22 5-arylazotropolone derivatives as potential XO inhibitors. In vitro enzyme-inhibitory assays for XO revealed that 3-nitro derivative 1j showed the most potent XO inhibitory activity, which is by one order of magnitude more potent than allopurinol. An enzyme-kinetic study revealed that 1j inhibited the production of uric acid by XO both competitively and non-competitively. A docking-simulation study of 1j with XO suggested that the carbonyl and hydroxyl groups of the tropolone ring interact with the hydroxy group that acts as a ligand for molybdenum and the amino acid residues around the active site of XO.

黄嘌呤氧化酶（XO）是一种在活性位点包含钼的酶，催化嘌呤碱氧化为尿酸。尽管XO抑制剂被广泛用于治疗高尿酸血症和痛风，但在临床上仅极少数的此类化合物被用作治疗这些疾病的药物。鉴于托酚酮独特的理化性质，即其螯合作用和与羧酸相似的pKa值，我们合成了22种潜在的XO抑制剂5-芳基偶氮酮化合物。XO的体外酶抑制试验表明，3-硝基衍生物1j表现出最有效的XO抑制活性，比别嘌呤醇的效力高一个数量级。酶动力学研究表明1jXO竞争性和非竞争性抑制了尿酸的产生。1j与XO的对接模拟研究表明，托酚酮环的羰基和羟基与充当钼配体的羟基和XO活性位点周围的氨基酸残基相互作用。