4.7 Article

Design, synthesis, and evaluation of tricyclic compounds containing phenyl-tetrazole as XOR inhibitors

期刊

出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114947

关键词

Phenyl-tetrazole; XOR inhibitors; Hypouricemic

向作者/读者索取更多资源

Tetrazole was used to replace the carboxyl-thiazole fragment of febuxostat to design three series of compounds as xanthine oxidoreductase (XOR) inhibitors. The inhibitory activity against XOR was evaluated, and compounds with significantly increased activity were identified. Molecular docking analysis showed that tetrazole could effectively replace the carboxyl group in the active cavity of XOR. In vivo studies in mice confirmed the hypouricemic effects of the most potent compounds identified. This study provides new insights and potential candidates for the design of XOR inhibitors.
Based on analyses of the interaction between febuxostat and xanthine oxidoreductase (XOR), tetrazole was used to replace the carboxyl-thiazole fragment of febuxostat using a bioelectronic isosteric strategy. Three series of compounds were designed. The inhibitory activity against XOR of all compounds was evaluated and their structure-activity relationships determined. The inhibitory activity against XOR of compounds I was weak, with a half-maximal inhibitory concentration (IC50) value > 10 mu mol, whereas the inhibitory activity of compounds II and III was increased significantly, among which compounds IIIa (IC50 = 26.3 +/- 1.21 nM) and IIIc (IC50 = 29.3 +/- 0.88 nM) were the best. Molecular docking showed that tetrazole could enter the active cavity instead of a carboxyl group and retain most of the interaction between febuxostat and XOR. For compounds III, the hydrogen bonds with Asn768 and Thr1010 of XOR were absent, but some new interactions were introduced to improve potency. A potassium oxazinate/hypoxanthine-induced model of acute hyperuricemia in mice also showed a significant hypouricemia effect of compounds IIIa, IIIc, and IIIe (P < 0.01), which was consistent with the results of inhibition in vitro. In conclusion, we identified a promising XOR inhibitor and provided new ideas for the design of XOR inhibitors.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据