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

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.

Synthesis,in vitroinhibitory activity, kinetic study and molecular docking of novelN-alkyl–deoxynojirimycin derivatives as potential α-glucosidase inhibitors

“…The method we used was reported before in our team 23 , α-glucosidase inhibitory activity was measured by using 0.1 mM phosphate buffer (pH 6.8) at 37 °C. The α-glucosidase enzyme (EC 3.2.1.20, 1 U/ml, 10 µL) in phosphate buffer was incubated with various concentrations of tested compounds (dissolved in 1% DMSO) at 37 °C for 20 min, then PNPG (10 mM, 20 µL) was added to the mixture as substrate.…”

“…The docking results were similar with previous studies. Zeng et al synthesised a series of N-benzyl-deoxynojirimycin derivatives, and the most active compound also established a p-p stacking interactions between molecules and enzymes, which gave the most active compound a strong inhibitory activity to a-glucosidase 23 . Besides, the hydrogen bonds between compounds a-glucosidase and were also played important roles in high activity on a-glucosidase.…”

“…13 A mixture of intermedial compounds 5 (1 mmol) or other intermedial compounds (6-24, respectively), 1-DNJ (1 mmol), K 2 CO 3 (2 mmol) in DMF was stirred at 85 C for 6 h. After the reaction completed, the mixture was concentrated under reduced pressure at 90 C. The product was purified by silica gel and thin layer chromatography to give the title compounds. The method we used was reported before in our team 23 , a-glucosidase inhibitory activity was measured by using 0.1 mM phosphate buffer (pH 6.8) at 37 C. The a-glucosidase enzyme (EC 3.2.1.20, 1 U/ ml, 10 mL) in phosphate buffer was incubated with various concentrations of tested compounds (dissolved in 1% DMSO) at 37 C for 20 min, then PNPG (10 mM, 20 mL) was added to the mixture as substrate. Finally, the absorbance was measured at 405 nm by using a spectrophotometer.…”

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“…The intrinsic instability of aminoacetal functionalities makes impractical the synthesis of iminosugar O -glycosides or of analogues having other heteroatom substituents at the pseudoanomeric position. Instead, aglycon-like appendages have been incorporated through N -substitution − and C -branching approaches, − which accounts for the two major subclasses of iminosugar derivatives on record.…”