Design, Synthesis, and Activity Evaluation of Novel -benzyl Deoxynojirimycin Derivatives for Use as α-Glucosidase Inhibitors.

To obtain α-glucosidase inhibitors with high activity, 19 NB-DNJDs (N-benzyl-deoxynojirimycin derivatives) were designed and synthesized. The results indicated that the 19 NB-DNJDs displayed different inhibitory activities towards α-glucosidase in vitro. Compound (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC value of 0.207 ± 0.11 mM, followed by (1-(3-bromo-4-hydroxy-5-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC: 0.276 ± 0.13 mM). Both IC values of and were significantly lower than that of acarbose (IC: 0.353 ± 0.09 mM). According to the structure-activity analysis, substitution of the benzyl and bromine groups on the benzene ring decreased the inhibition activity, while methoxy and hydroxyl group substitution increased the activity, especially with the hydroxyl group substitution. Molecular docking results showed that three hydrogen bonds were formed between compound and amino acids in the active site of α-glucosidase. Additionally, an arene‒arene interaction was also modelled between the phenyl ring of compound and Arg 315. The three hydrogen bonds and the arene‒arene interaction resulted in a low binding energy (-5.8 kcal/mol) and gave a higher inhibition activity. Consequently, compound is a promising candidate as a new α-glucosidase inhibitor for the treatment of type Ⅱ diabetes.