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

Zeng Zeng,Wang Wang,Lin Lin,Nie Nie,Lu Lu,Peng Peng,Chen Chen,Yin Yin

doi:10.3390/molecules24183309

Zeng Zeng, Wang Wang + Show 6 more

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https://doi.org/10.3390/molecules24183309

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Abstract

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 18a (1-(4-hydroxy-3-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol) showed the highest activity, with an IC50 value of 0.207 ± 0.11 mM, followed by 18b (1-(3-bromo-4-hydroxy-5-methoxybenzyl)-2-(hydroxymethyl) piperidine-3,4,5-triol, IC50: 0.276 ± 0.13 mM). Both IC50 values of 18a and 18b were significantly lower than that of acarbose (IC50: 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 18a and amino acids in the active site of α-glucosidase. Additionally, an arene–arene interaction was also modelled between the phenyl ring of compound 18a and Arg 315. The three hydrogen bonds and the arene–arene interaction resulted in a low binding energy (−5.8 kcal/mol) and gave 18a a higher inhibition activity. Consequently, compound 18a is a promising candidate as a new α-glucosidase inhibitor for the treatment of type Ⅱ diabetes.

Highlights

Iminosugars are carbohydrate mimics in which the endocyclic oxygen has been replaced with a nitrogen atom
1-DNJ were synthesized according to the methods of Wennekes and Matos with slight modification using 2,3,4,5-tetra-O-benzyl-d-glucopyranose as the starting compound [13,17,18]
The results showed that compound 18a was the most potent α-glucosidase inhibitor and may be useful for treating type II diabetes

Summary

Introduction

Iminosugars are carbohydrate mimics in which the endocyclic oxygen has been replaced with a nitrogen atom. Some iminosugars are regarded as potential inhibitors of glycosidase. It has been reported that the bioactivity of iminosugars is related to their ability to mimic the transition state of pyranosidic or furanosidic units of the natural substrate during glycosidic bond cleavage [1,2]. The first generation of iminosugars came from the discovery of nojirimycin (NJ) and its biological activity on both α- and β-glucosidase. The presence of a hydroxyl group at C-1 results in the instability of NJ [1]. A more stable glucosidase inhibitor named 1-deoxynojirimycin(1-DNJ)

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