State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Eur J Med Chem. 2018 May 10;151:849-860. doi: 10.1016/j.ejmech.2018.01.096. Epub 2018 Feb 2.
Xanthine oxidase, which catalyzes the oxidative reaction of hypoxanthine and xanthine into uric acid, is a key enzyme to the pathogenesis of hyperuricemia and gout. In this study, for the purpose of discovering novel xanthine oxidase (XO) inhibitors, a series of 2-arylbenzo[b]furan derivatives (3a-3d, 4a-4o and 6a-6d) were designed and synthesized. All these compounds were evaluated their xanthine oxidase inhibitory and antioxidant activities by using in vitro enzymatic assay and cellular model. The results showed that a majority of the designed compounds exhibited potent xanthine oxidase inhibitory effects and antioxidant activities, and compound 4a emerged as the most potent xanthine oxidase inhibitor (IC = 4.45 μM). Steady-state kinetic measurements of the inhibitor 4a with the bovine milk xanthine oxidase indicated a mixed type inhibition with 3.52 μM K and 13.14 μM K, respectively. The structure-activity relationship analyses have also been presented. Compound 4a exhibited the potent hypouricemic effect in the potassium oxonate-induced hyperuricemic mice model. A molecular docking study of compound 4a was performed to gain an insight into its binding mode with xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious in treatment of gout.
黄嘌呤氧化酶能够催化次黄嘌呤和黄嘌呤氧化生成尿酸，是高尿酸血症和痛风发病机制的关键酶。在这项研究中，为了发现新型黄嘌呤氧化酶（XO）抑制剂，设计并合成了一系列 2-芳基苯并[b]呋喃衍生物（3a-3d、4a-4o 和 6a-6d）。所有这些化合物均通过体外酶促测定和细胞模型评估了其黄嘌呤氧化酶抑制和抗氧化活性。结果表明，大多数设计的化合物表现出很强的黄嘌呤氧化酶抑制作用和抗氧化活性，化合物 4a 表现出最强的黄嘌呤氧化酶抑制活性（IC50=4.45μM）。抑制剂 4a 与牛乳黄嘌呤氧化酶的稳态动力学测量表明，其抑制类型为混合型，K 分别为 3.52μM 和 13.14μM。还呈现了结构-活性关系分析。化合物 4a 在氧嗪酸钾诱导的高尿酸血症小鼠模型中表现出很强的降血尿酸作用。对化合物 4a 进行了分子对接研究，以深入了解其与黄嘌呤氧化酶的结合模式。这些结果突出了新型黄嘌呤氧化酶抑制剂的鉴定，它们在痛风治疗中可能更有效。
