H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan.
Bioorg Chem. 2018 Sep;79:201-211. doi: 10.1016/j.bioorg.2018.04.021. Epub 2018 May 1.
5-Aryl-1H-tetrazoles (1-24) were synthesized and screened for their xanthine oxidase (XO) inhibitory activity using allopurinol as standard inhibitor (IC = 2.0 ± 0.01 µM). Six compounds 3, 4, 5, 9, 21, and 24 exhibited significant to weak activities with IC values in the range of 7.4-174.2 µM. Active compounds were further subjected to kinetic and molecular docking studies to deduce their modes of inhibition, and to study their interactions with the protein (XO) at atomic level, respectively. Interestingly, all these compounds showed a competitive mode of inhibition. Docking studies identified several important interactions between the ligand and the receptor protein (XO). Some of these interactions were similar to that exhibited by clinical inhibitors of XO (allopurinol, and febuxostat). This study identifies 5-aryl-1H-tetrazoles as a new class of xanthine oxidase inhibitors, which deserves to be further, investigated for the treatment of hyperuricemia and gout.
5-芳基-1H-四唑（1-24）被合成，并使用别嘌醇作为标准抑制剂（IC=2.0±0.01µM）对其黄嘌呤氧化酶（XO）抑制活性进行筛选。六种化合物 3、4、5、9、21 和 24 表现出显著至弱的活性，IC 值范围为 7.4-174.2µM。活性化合物进一步进行了动力学和分子对接研究，以推断它们的抑制模式，并在原子水平上研究它们与蛋白质（XO）的相互作用。有趣的是，所有这些化合物都表现出竞争性抑制模式。对接研究确定了配体和受体蛋白（XO）之间的几个重要相互作用。其中一些相互作用与 XO 的临床抑制剂（别嘌醇和非布司他）相似。这项研究将 5-芳基-1H-四唑鉴定为一种新型的黄嘌呤氧化酶抑制剂，值得进一步研究用于治疗高尿酸血症和痛风。
