Synthesis, in vitro inhibitory activity, kinetic study and molecular docking of novel N-alkyl-deoxynojirimycin derivatives as potential α-glucosidase inhibitors

• Published in: Journal of enzyme inhibition and medicinal chemistry Vol. 35; no. 1; pp. 1879 - 1890
• Main Authors: Lin, Ping, Zeng, Jia-Cheng, Chen, Ji-Guang, Nie, Xu-Liang, Yuan, En, Wang, Xiao-Qiang, Peng, Da-Yong, Yin, Zhong-Ping
• Format: Journal Article
• Language: English
• Published: ABINGDON Taylor & Francis 01.01.2020; Taylor & Francis Ltd; Taylor & Francis Group
• Subjects: 1-Deoxynojirimycin - chemical synthesis; 1-Deoxynojirimycin - pharmacokinetics; 1-Deoxynojirimycin derivatives; Acarbose; Acarbose - pharmacology; Acarbose - standards; Acids; alpha-Glucosidases - metabolism; Benzylidene Compounds - chemistry; Biochemistry & Molecular Biology; Carbon; Chemistry, Medicinal; Diabetes; docking study; Electrostatic properties; Functional foods & nutraceuticals; Glucosamine - analogs & derivatives; Glucosamine - chemical synthesis; Glucosamine - pharmacokinetics; Glycoside Hydrolase Inhibitors - chemical synthesis; Glycoside Hydrolase Inhibitors - pharmacokinetics; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; inhibitor; Kinases; Kinetics; Laboratories; Life Sciences & Biomedicine; Molecular Docking Simulation; Natural products; Pharmacology & Pharmacy; Pharmacy; Research Paper; Science & Technology; Structure-Activity Relationship; α-Glucosidase; alpha-glucosidase; docking study; inhibitor; 1-Deoxynojirimycin derivatives; structure-activity relationship; structure–activity relationship; α-glucosidase
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2020.1826941

A series of novel N-alkyl-1-deoxynojirimycin derivatives 25 ∼ 44 were synthesised and evaluated for their in vitro α-glucosidase inhibitory activity to develop α-glucosidase inhibitors with high activity. All twenty compounds exhibited α-glucosidase inhibitory activity with IC 50 values ranging from 30.0 ± 0.6 µM to 2000 µM as compared to standard acarbose (IC 50 = 822.0 ± 1.5 µM). The most active compound 43 was ∼27-fold more active than acarbose. Kinetic study revealed that compounds 43, 40, and 34 were all competitive inhibitors on α-glucosidase with K i of 10 µM, 52 µM, and 150 µM, respectively. Molecular docking demonstrated that the high active inhibitors interacted with α-glucosidase by four types of interactions, including hydrogen bonds, π-π stacking interactions, hydrophobic interactions, and electrostatic interaction. Among all the interactions, the π-π stacking interaction and hydrogen bond played a significant role in a various range of activities of the compounds.