Xanthine oxidase is a key enzyme that catalyses hypoxanthine and xanthine to uric acid, whose overproduction leads to the gout-causing hyperuricemia. In this study, a series of 1-hydroxy/methoxy-4-methyl-2-phenyl-1H-imidazole-5-carboxylic acid derivatives (4a-4k and 6a-6k) was synthesized and evaluated for their inhibitory potency against xanthine oxidase. The 1-hydroxyl substituted derivatives 4a-4k showed excellent inhibitory potency with IC50 values ranging from 0.003 μM to 1.2 μM, with compounds 4d (IC₅₀ = 0.003 μM), 4e (IC₅₀ = 0.003 μM), and 4f (IC₅₀ = 0.006 μM) manifesting the most potent xanthine oxidase inhibitory potency that were comparable with that of Febuxostat (IC₅₀ = 0.01 μM). Lineweaver-Burk plot analysis revealed that representative compound 4f acted as a mixed-type inhibitor for xanthine oxidase. The basis of significant inhibition of xanthine oxidase by 4f was rationalized by its molecular docking into the active site of xanthine dehydrogenase.

中文翻译：

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非嘌呤黄嘌呤氧化酶抑制剂1-羟基/甲氧基-4-甲基-2-苯基-1H-咪唑-5-羧酸衍生物的合成与评价。

黄嘌呤氧化酶是将次黄嘌呤和黄嘌呤催化为尿酸的关键酶，其过度生产会导致痛风引起的高尿酸血症。在这项研究中，合成了一系列的1-羟基/甲氧基-4-甲基-2-苯基-1H-咪唑-5-羧酸衍生物（4a-4k和6a-6k）并评估了它们对黄嘌呤氧化酶的抑制作用。1-羟基取代的衍生物4a-4k表现出优异的抑制效能，IC50值在0.003μM至1.2μM之间，化合物4d（IC₅₀= 0.003μM），4e（IC₅₀= 0.003μM）和4f（IC₅₀= 0.006μM）表现出与非布索坦（IC pot = 0.01μM）相当的最强的黄嘌呤氧化酶抑制能力。Lineweaver-Burk图分析表明，代表性化合物4f充当了黄嘌呤氧化酶的混合型抑制剂。