Design, synthesis and biological evaluation of 1-hydroxy-2-phenyl-4pyridyl-1H-imidazole derivatives as xanthine oxidase inhibitors

被引:40
作者
Zhang, Tingjian [1 ,2 ]
Lv, Yunying [1 ]
Lei, Yu [1 ]
Liu, Dan [1 ]
Feng, Yao [1 ]
Zhao, Jiaxing [1 ]
Chen, Shaolei [1 ]
Meng, Fanhao [2 ]
Wang, Shaojie [1 ]
机构
[1] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Key Lab Struct Based Drugs Design & Discovery, Minist Educ, 103 Culture Rd, Shenyang 110016, Liaoning, Peoples R China
[2] China Med Univ, Sch Pharm, 77 Puhe Rd, Shenyang 110122, Liaoning, Peoples R China
关键词
1-Hydroxy-2-phenyl-4-pyridyl-1H-imidazole; Synthesis; Xanthine oxidase inhibitor; Hyperuricemia; ACID-DERIVATIVES; POTENT INHIBITOR; OXIDOREDUCTASE; DISCOVERY; HYPERURICEMIA; OPTIMIZATION; ALLOPURINOL; MECHANISM; EFFICACY; 3D-QSAR;
D O I
10.1016/j.ejmech.2018.01.060
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase inhibitory potency. As a continuation study, a series of 1-hydroxy-2-phenyl-1H-imidazole derivatives containing a pyridine moiety (4a-g and 5a-g) at the 4-position was designed and synthesized. Evaluation of in vitro xanthine oxidase inhibition demonstrated that the 4a-g series was more potent than the 5a-g series. Compound 4f was the most promising derivative in the series with an IC50 value of 0.64 mu M. A Lineweaver-Burk plot revealed that compound 4f acted as a mixed-type xanthine oxidase inhibitor. An iso-pentyloxy group at the 4'-position improved the inhibitory potency. More interestingly, structure-activity relationship analysis indicated that the pyridine para-N atom played a crucial role in the inhibition. Molecular modeling provided a reasonable explanation for the structure-activity relationships observed in this study. In addition, a three dimensional quantitative structure-activity relationships model which possessed reasonable statistics (q(2) = 0.885 and r(2) = 0.993) was conducted to further understand the structural basis of these compounds as xanthine oxidase inhibitors. These compounds, especially compound 4f, have good potential for further investigations. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:668 / 677
页数:10
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