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

• Published in: European journal of medicinal chemistry 2018-02, Vol.146, p.668-677
• Main Authors: Zhang, Tingjian, Lv, Yunying, Lei, Yu, Liu, Dan, Feng, Yao, Zhao, Jiaxing, Chen, Shaolei, Meng, Fanhao, Wang, Shaojie
• Format: Article
• Language: English
• Subjects: 1-Hydroxy-2-phenyl-4-pyridyl-1H-imidazole; Animals; Cattle; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hyperuricemia; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Models, Molecular; Molecular Structure; Quantitative Structure-Activity Relationship; Synthesis; Xanthine Oxidase - antagonists & inhibitors; Xanthine Oxidase - metabolism; Xanthine oxidase inhibitor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.01.060

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 μM. 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 (q2 = 0.885 and r2 = 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. [Display omitted] •1-Hydroxy-2-phenyl-4-pyridyl-1H-imidazole derivatives were synthesized.•Compound 4f showed a promising XO inhibitory potency with an IC50 value of 0.64 μM.•The structure–activity relationships of the synthesized compounds were summarized.•Molecular modeling and Steady-state kinetic analysis were performed.•3D-QSAR model was conducted.