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Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel alpha-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation

文献类型：期刊论文

作者Xie, Hong-Xu1; Zhang, Juan1; Li, Yue1; Zhang, Jin-He1; Liu, Shan-Kui1; Zhang, Jie2; Zheng, Hua2; Hao, Gui-Zhou2; Zhu, Kong-Kai1,3; Jiang, Cheng-Shi1
刊名BIOORGANIC CHEMISTRY
出版日期2021-10-01
卷号115页码:17
关键词Tetrahydrobenzo[b]thiophen-2-yl)urea alpha-Glucosidase inhibitors Non-competitive inhibitor Molecular docking Anti-hyperglycaemic activity Type 2 diabetes
ISSN号0045-2068
DOI10.1016/j.bioorg.2021.105236
通讯作者Hao, Gui-Zhou(haoguizhouhgz@163.com) ; Zhu, Kong-Kai(bio_zhukk@ujn.edu.cn) ; Jiang, Cheng-Shi(bio_jiangcs@ujn.edu.cn)
英文摘要alpha-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of alpha-glucosidase inhibitors with tetrahydrobenzo[b]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated alpha-glucosidase inhibitors, 5a, and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against alpha-glucosidase than the parental compound 5a (IC50 of 26.71 +/- 1.80 mu M) and the positive control acarbose (IC50 of 258.53 +/- 1.27 mu M). Among them, compounds 8r (IC50 = 0.59 +/- 0.02 mu M) and 8s (IC50 = 0.65 +/- 0.03 mu M) were the most potent inhibitors, and showed selectivity over alpha-amylase. The direct binding of both compounds with alpha-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of alpha-glucosidase. In addition, compounds 8r and 8s were not toxic (IC50 > 100 mu M) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[b]thiophen-2-yl)urea chemotype for developing novel alpha-glucosidase inhibitors against type 2 diabetes.
WOS关键词DIABETES-MELLITUS ; DYNAMICS ; ANALOGS ; POTENT ; RISK
资助项目Natural Science Foundation of Shandong Province[ZR2019YQ31] ; Natural Science Foundation of Shandong Province[ZR2020MB103] ; National Natural Science Foundation of China[21672082] ; Major Science and Technology Innovation Project of Shandong Province[2019JZZY011116] ; Science and Technology Project of University of Jinan[XKY2004]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
WOS记录号WOS:000704036500003
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
源URL[http://119.78.100.183/handle/2S10ELR8/297493]  
专题新药研究国家重点实验室
通讯作者Hao, Gui-Zhou; Zhu, Kong-Kai; Jiang, Cheng-Shi
作者单位1.Jinan Univ, Sch Biol Sci & Technol, Jinan 250022, Peoples R China
2.Lunan Pharmaceut Grp Co Ltd, Linyi 273400, Shandong, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Xie, Hong-Xu,Zhang, Juan,Li, Yue,et al. Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel alpha-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation[J]. BIOORGANIC CHEMISTRY,2021,115:17.
APA Xie, Hong-Xu.,Zhang, Juan.,Li, Yue.,Zhang, Jin-He.,Liu, Shan-Kui.,...&Jiang, Cheng-Shi.(2021).Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel alpha-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation.BIOORGANIC CHEMISTRY,115,17.
MLA Xie, Hong-Xu,et al."Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel alpha-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation".BIOORGANIC CHEMISTRY 115(2021):17.

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来源：上海药物研究所

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