Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, PR China.
Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, 430205, PR China; School of Materials Science and Engineering, Zhengzhou University, No.100 Science Avenue, Zhengzhou City, 450001, Henan Province, PR China.
Eur J Med Chem. 2024 May 5;271:116443. doi: 10.1016/j.ejmech.2024.116443. Epub 2024 Apr 26.
Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC value of 0.13 μM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC = 2.93 μM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.
黄嘌呤氧化酶（XO）是人体内尿酸生成的关键酶。XO 抑制剂（XOIs）临床上用于治疗高尿酸血症和痛风，因为它们可以有效抑制尿酸的生成。先前的研究表明，吲哚和异恶唑衍生物都对 XO 具有良好的抑制作用。在这里，我们根据生物等排替换和杂化策略设计并合成了一系列新型的 N-5-（1H-吲哚-5-基）异恶唑-3-羧酸。在所得到的目标化合物中，化合物 6c 对 XO 的抑制活性最好，IC 值为 0.13 μM，比经典的抗痛风药物别嘌醇（IC = 2.93 μM）高 22 倍。构效关系分析表明，吲哚环氮原子上的疏水性基团对于目标化合物对 XO 的抑制活性是必需的。酶动力学研究证明，化合物 6c 是一种混合类型的 XOI。分子对接研究表明，目标化合物 6c 不仅可以保留与 XO 结合部位类似的非布司他的关键相互作用，还可以产生一些新的相互作用，如异恶唑环上的氧原子与氨基酸残基 Ser876 和 Thr1010 之间的两个氢键。这些结果表明，5-（1H-吲哚-5-基）异恶唑-3-羧酸可能是设计新型 XOIs 的有效骨架，化合物 6c 有可能成为进一步开发新型抗痛风候选药物的先导化合物。
