Dataset Information

Study on the interaction of triaryl-dihydro-1,2,4-oxadiazoles with ?-glucosidase.

ABSTRACT:

Purpose

One of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through ?-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic ?-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular and microvascular complications. This study aimed to synthesize 2-aryl-4,6-diarylpyrimidine derivatives, screen their ?-glucosidase inhibitory activity, perform kinetic and molecular docking studies.

Methods

A series of 3,4,5-triphenyl-4,5-dihydro-1,2,4-oxadiazole derivatives were synthesized and their ?-glucosidase inhibitory activity was screened in vitro. Compounds 6a-k were synthesized via a two-step reaction with a yield between 65 and 88%. The structural elucidation of the synthesized derivatives was performed by different spectroscopic techniques. ?-Glucosidase inhibitory activity of the oxadiazole derivatives 6a-k was evaluated against Saccharomyces cerevisiae ?-glucosidase.

Results

Most of the synthesized compounds demonstrated ?-glucosidase inhibitory action. Particularly compounds 6c, 6d and 6 k were the most active compounds with IC₅₀ values 215?±?3, 256?±?3, and 295?±?4 ?M respectively. A kinetic study performed for compound 6c revealed that the compound is a competitive inhibitor of Saccharomyces cerevisiae ?-glucosidase with K_i of 122 ?M. The docking study also revealed that the two compounds, 6c and 6 k, have important binding interactions with the enzyme active site.

Conclusion

The overall results of our study reveal that the synthesized compounds could be a potential candidate in the search for novel ?-glucosidase inhibitors to manage the postprandial hyperglycemia incidence. Graphical abstract.

SUBMITTER: Khosravi A

PROVIDER: S-EPMC7214590 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Study on the interaction of triaryl-dihydro-1,2,4-oxadiazoles with α-glucosidase.

Khosravi Arefeh A Vaezi Gholamhassan G Hojati Vida V Abdi Khosrou K

Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences 20200106 1

<h4>Purpose</h4>One of the therapeutic approaches in the management of Type 2 diabetes is delaying the absorption of glucose through α-glucosidase enzymes inhibition, which can reduce the incidence of postprandial hyperglycemia. The existence of chronic postprandial hyperglycemia impaired the endogenous antioxidant defense due to inducing oxidative stress induced pancreatic β-cell destruction through uncontrolled free radicals generation such as ROS, which in turn, leads to various macrovascular ...[more]

PMID: 31907787

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Project description:There is an increasing prevalence of diabetes mellitus throughout the world, and new compounds are necessary to combat this. The currently available antidiabetic therapies are long-term complicated and side effect-prone, and this has led to a demand for more affordable and more effective methods of tackling diabetes. Research is focused on finding alternative medicinal remedies with significant antidiabetic efficacy as well as low adverse effects. In this research work, we have focused our efforts to synthesize a series of 1,2,4-triazole-based bis-hydrazones and evaluated their antidiabetic properties. In addition, the precise structures of the synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H-NMR, 13C-NMR, and HREI-MS. To find the antidiabetic potentials of the synthesized compounds, in vitro α-glucosidase and α-amylase inhibitory activities were characterized using acarbose as the reference standard. From structure-activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both α-amylase and α-glucosidase enzymes was due to the different substitution patterns of the substituent(s) at variable positions of both aryl rings A and B. The results of the antidiabetic assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values ranging from 0.70 ± 0.05 to 35.70 ± 0.80 μM (α-amylase) and 1.10 ± 0.05 to 30.40 ± 0.70 μM (α-glucosidase). The obtained results were compared to those of the standard acarbose drug (IC50 = 10.30 ± 0.20 μM for α-amylase and IC50 = 9.80 ± 0.20 μM for α-glucosidase). Specifically, compounds 17, 15, and 16 were found to be significantly active with IC50 values of 0.70 ± 0.05, 1.80 ± 0.10, and 2.10 ± 0.10 μM against α-amylase and 1.10 ± 0.05, 1.50 ± 0.05, and 1.70 ± 0.10 μM against α-glucosidase, respectively. These findings reveal that triazole-containing bis-hydrazones act as α-amylase and α-glucosidase inhibitors, which help develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic agents.