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Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against beta-glucosidase

文献类型：期刊论文

作者Liu, Xu4; Li, Fengxin4; Su, Lulu4; Wang, Mingchen1,2,3; Jia, Tongguan4; Xu, Xiaoming4; Li, Xiaoliu4; Wei, Chao4; Luo, Cheng2,3; Chen, Shijie2,3
刊名BIOORGANIC CHEMISTRY
出版日期2022-10-01
卷号127页码:6
ISSN号0045-2068
关键词Benzimidazole-iminosugars Glucosidase inhibitors Suzuki coupling reaction Inhibition type Solvent-exposed region
DOI10.1016/j.bioorg.2022.106016
通讯作者Chen, Hua(hua-todd@163.com)
英文摘要A series of novel benzimidazole-iminosugars linked a (substuituted) phenyl group on benzene ring of benzimidazole 5(a-p) and 6(a-p) have been rationally designed and conveniently synthesized through Suzuki coupling reaction in high yields. All compounds have been evaluated for their inhibitory activities against beta-glucosidase (almond). Six compounds 5d, 6d, 6e, 6i, 6n, and 6p showed more significant inhibitory activities with IC50 values in the range of 0.03-0.08 mu M, almost 10-fold improved than that of the parent analogue 4, and much higher than that of the positive control castanospermine. The additional phenyl ring and the electron donating groups on it would be beneficial for the activity. Compounds 6d, 6n, and 4 had been chosen to be tested for their inhibition types against beta-glucosidase. Interestingly, three compounds have different inhibition types although they had very similar structure. Their K-i values were calculated to be 0.02 +/- 0.01 mu M, 0.02 +/- 0.01 mu M, and 0.66 +/- 0.14 mu M, respectively. The equilibrium dissociation constant (K-D) for 6d, 6n, and 4 and beta-glucosidase was 0.04 mu M, 0.03 mu M and 0.45 mu M by the ITC-based assay, respectively. Molecular docking work suggests that such benzimidazole-iminosugars derivatives might bind to the active site of beta-glucosidase mainly through hydrogen bonds, the additional phenyl ring towards the solvent-exposed region played an important effect on their inhibitory activity against beta-glucosidase.
WOS关键词GLYCOSIDASE INHIBITORS ; THIAZINAN-4-ONE ; DERIVATIVES ; PICOMOLAR ; BINDING
资助项目National Natural Science Foundation of China (NSFC)[21772031] ; Natural Science Foundations of Hebei Province[B2019201398]
WOS研究方向Biochemistry & Molecular Biology ; Chemistry
语种英语
出版者ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号WOS:000830919700003
源URL[http://119.78.100.183/handle/2S10ELR8/301995]  
专题中国科学院上海药物研究所
通讯作者Chen, Hua
作者单位1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Chem Biol, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China
4.Hebei Univ, Coll Chem & Environm Sci, Key Lab Chem Biol Hebei Prov, Baoding 071002, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xu,Li, Fengxin,Su, Lulu,et al. Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against beta-glucosidase[J]. BIOORGANIC CHEMISTRY,2022,127:6.
APA Liu, Xu.,Li, Fengxin.,Su, Lulu.,Wang, Mingchen.,Jia, Tongguan.,...&Chen, Hua.(2022).Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against beta-glucosidase.BIOORGANIC CHEMISTRY,127,6.
MLA Liu, Xu,et al."Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against beta-glucosidase".BIOORGANIC CHEMISTRY 127(2022):6.

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来源：上海药物研究所

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