Discovery of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives as novel xanthine oxidase inhibitors
Discovery of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives as novel xanthine oxidase inhibitors
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发现 4-(苯氧基甲基)-1H-1,2,3-三唑衍生物作为新型黄嘌呤氧化酶抑制剂
DOI：
10.1016/j.bmcl.2022.128582
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发表时间：
2022
影响因子：
2.7
通讯作者：
Meng Fan-hao
中科院分区：
文献类型：
--
作者：
Zhang Ting-jian;Zhang Yi;Zhang Zhen-hao;Wang Zhao-ran;Zhang Xu;Hu Sen-sen;Lu Peng-fei;Guo Shuai;Meng Fan-hao
设计、合成了一系列4-苯氧甲基-1H-1，2，3-三唑类化合物，并评价了其对黄嘌呤氧化酶（XO）的抑制活性。在这些化合物中，9 mememerged是最有效的XO抑制剂，IC 50值为0.70 μM，比别嘌呤醇强约14倍。此外，化合物9 m显示出有利的药物样性质，配体效率（LE）和亲脂性配体效率（LLE）值分别为0.33和3.41。通过分子对接和分子动力学研究进一步探讨了9 min复合物与XO的结合方式，体内低尿酸血症研究也表明9 min复合物可以有效降低大鼠血清尿酸水平。综上所述，化合物9 m可能是进一步开发XO抑制剂的有希望的先导。
A series of 4-(phenoxymethyl)-1H-1,2,3-triazole derivatives were designed, synthesized, and evaluated for their xanthine oxidase (XO) inhibitory activities. Among these compounds,9memerged as the most effective XO inhibitor with an IC50value of 0.70 μM, which was approximately 14-fold more potent than allopurinol. Additionally, compound9mdisplayed favorable drug-like properties with ligand efficiency (LE) and lipophilic ligand efficiency (LLE) values of 0.33 and 3.41, respectively. We further explored the binding mode of9min complex with XO by molecular docking and molecular dynamics studies.In vivohypouricemic studies also suggested that9mcould effectively lower the serum uric acid levels of rat. In summary, compound9mcould be a promising lead for further development of XO inhibitors.