Xanthine oxidase (XO) is a critical target for the therapy of hyperuricemia and gout. In this study, a number of 3-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones (3a-3w) were newly designed by a bioisosteric replacement and hybrid strategy with the hope of obtaining novel and effective nonpurine XO inhibitors. Subsequently, these compounds were synthesized through a three-step procedure, with good yields. In addition, the in vitro bovine XO inhibitions were measured by spectrophotometric determination of uric acid formation at 295 nm using allopurinol as a positive control. As a result, compound 3j was found to be the most potent XO inhibitor, with an IC50 value of 0.121 µM, which was approximately 63-fold more potent than allopurinol, and the analysis of the structure-activity relationships indicated that the hydrophobic group at 4'-position was essential for inhibitory potency. Additionally, the molecular modeling results showed that the 1,2,4-oxadiazol-5(4H)-one moiety binds to XO active site via various hydrogen bonds with Arg880 and Thr1010. Moreover, the compound 3j was demonstrated to be a mixed-type nonpurine XO inhibitor. Furthermore, the hypouricemic studies on a rat model, induced by potassium oxonate, demonstrated that serum uric acid levels could be effectually reduced by compound 3j at an oral dose of 15 mg/kg. Therefore, compound 3j could be a promising lead compound for the treatment of hyperuricemia and gout.

中文翻译：

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新型的3- [4-烷氧基-3-（1H-四唑-1-基）苯基] -1,2,4-恶二唑-5（4H）-作为黄嘌呤氧化酶抑制剂：设计，合成和生物学评估。

黄嘌呤氧化酶（XO）是治疗高尿酸血症和痛风的关键靶标。在这项研究中，新设计了一些3- [4-烷氧基-3-（1H-四唑-1-基）苯基] -1,2,4-恶二唑-5（4H）-一（3a-3w）通过生物等位替代和混合策略，希望获得新型有效的非嘌呤XO抑制剂。随后，通过三步法合成了这些化合物，收率很高。另外，使用别嘌呤醇作为阳性对照，通过分光光度法测定在295 nm处的尿酸形成来测量体外牛XO抑制作用。结果，发现化合物3j是最有效的XO抑制剂，IC50值为0.121 µM，比别嘌呤醇的效价高约63倍，结构-活性关系的分析表明，在4'-位的疏水基团对于抑制效能是必不可少的。此外，分子建模结果表明，1,2,4-恶二唑-5（4H）-one部分通过与Arg880和Thr1010的各种氢键结合到XO活性位。此外，化合物3j被证明是混合型非嘌呤XO抑制剂。此外，由草酸钾诱导的对大鼠模型的降尿酸研究表明，口服剂量为15 mg / kg的化合物3j可有效降低血清尿酸水平。因此，化合物3j可能是治疗高尿酸血症和痛风的有前途的先导化合物。4-恶二唑-5（4H）-one部分通过与Arg880和Thr1010的各种氢键结合到XO活性位。此外，化合物3j被证明是混合型非嘌呤XO抑制剂。此外，由草酸钾诱导的对大鼠模型的降尿酸研究表明，口服剂量为15 mg / kg的化合物3j可有效降低血清尿酸水平。因此，化合物3j可能是治疗高尿酸血症和痛风的有前途的先导化合物。4-恶二唑-5（4H）-one部分通过与Arg880和Thr1010的各种氢键结合到XO活性位。此外，化合物3j被证明是混合型非嘌呤XO抑制剂。此外，由草酸钾诱导的对大鼠模型的降尿酸研究表明，口服剂量为15 mg / kg的化合物3j可有效降低血清尿酸水平。因此，化合物3j可能是治疗高尿酸血症和痛风的有前途的先导化合物。