Liu Xu, Li Fengxin, Su Lulu, Wang Mingchen, Jia Tongguan, Xu Xiaoming, Li Xiaoliu, Wei Chao, Luo Cheng, Chen Shijie, Chen Hua
Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding 071002, China.
The Center for Chemical Biology, Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
Bioorg Chem. 2022 Oct;127:106016. doi: 10.1016/j.bioorg.2022.106016. Epub 2022 Jul 9.
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 β-glucosidase (almond). Six compounds 5d, 6d, 6e, 6i, 6n, and 6p showed more significant inhibitory activities with IC values in the range of 0.03-0.08 μM, 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 β-glucosidase. Interestingly, three compounds have different inhibition types although they had very similar structure. Their K values were calculated to be 0.02 ± 0.01 μM, 0.02 ± 0.01 μM, and 0.66 ± 0.14 μM, respectively. The equilibrium dissociation constant (K) for 6d, 6n, and 4 and β-glucosidase was 0.04 μM, 0.03 μM and 0.45 μM by the ITC-based assay, respectively. Molecular docking work suggests that such benzimidazole-iminosugars derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds, the additional phenyl ring towards the solvent-exposed region played an important effect on their inhibitory activity against β-glucosidase.
一系列新型苯并咪唑 - 亚氨基糖，其在苯并咪唑5(a - p)和6(a - p)的苯环上连接了一个（取代的）苯基，已通过铃木偶联反应合理设计并方便地以高产率合成。所有化合物均已针对其对β - 葡萄糖苷酶（杏仁）的抑制活性进行了评估。六种化合物5d、6d、6e、6i、6n和6p表现出更显著的抑制活性，IC值在0.03 - 0.08 μM范围内，比母体类似物4提高了近10倍，且远高于阳性对照栗精胺。额外的苯环及其上的供电子基团对活性有益。已选择化合物6d、6n和4来测试它们对β - 葡萄糖苷酶的抑制类型。有趣的是，尽管这三种化合物结构非常相似，但它们具有不同的抑制类型。计算得出它们的K值分别为0.02±0.01 μM、0.02±0.01 μM和0.66±0.14 μM。通过基于等温滴定量热法（ITC）的测定，6d、6n和4与β - 葡萄糖苷酶的平衡解离常数（K）分别为0.04 μM、0.03 μM和0.45 μM。分子对接研究表明，此类苯并咪唑 - 亚氨基糖衍生物可能主要通过氢键与β - 葡萄糖苷酶的活性位点结合，朝向溶剂暴露区域的额外苯环对其对β - 葡萄糖苷酶的抑制活性起重要作用。
