Exploring the Dual Inhibitory Activity of Novel Anthranilic Acid Derivatives towards α-Glucosidase and Glycogen Phosphorylase Antidiabetic Targets: Design, In Vitro Enzyme Assay, and Docking Studies.

Saleh Ihmaid

doi:10.3390/molecules23061304

Abstract

A few new anthranilate diamide derivatives, 3a–e, 5a–c and 7a–d, were designed, synthesized, and evaluated for their inhibitory activity against two interesting antidiabetic targets, α-glucosidase and glycogen phosphorylase enzymes. Different instrumental analytical tools were applied in identification and conformation of their structures like; 13C NMR, 1H NMR and elemental analysis. The screening of the novel compounds showed potent inhibitory activity with nanomolar concentration values. The most active compounds (5c) and (7b) showed the highest inhibitory activity against α-glucosidase and glycogen phosphorylase enzymes IC50 = 0.01247 ± 0.01 µM and IC50 = 0.01372 ± 0.03 µM, respectively. In addition, in vivo testing of the highly potent α-glucosidase inhibitor (7b) on rats with DTZ-induced diabetes was done and showed significant reduction of blood glucose levels compared to the reference drug. Furthermore, a molecular docking study was performed to help understand the binding interactions of the most active analogs with these two enzymes. The data obtained from the molecular modeling were correlated with those obtained from the biological screening. These data showed considerable antidiabetic activity for these newly synthesized compounds.

Highlights

Diabetes mellitus disease is a chronic condition in which the human body is unable to produce adequate insulin hormone type 1 or is a hyperglycemia that is uncontrolled with endogenous available insulin type 2 and clinically characterized by aberrant elevated levels of glucose in the blood [1,2,3]
It has recently been reported that 21% of patients will fail on metformin treatment within five years [13,14]
Nuclear magnetic resonance (NMR) spectral results are recorded as chemical shifts (d) relative to the internal transcranial magnetic stimulation (TMS)

Summary

Introduction

Diabetes mellitus disease is a chronic condition in which the human body is unable to produce adequate insulin hormone type 1 or is a hyperglycemia that is uncontrolled with endogenous available insulin type 2 and clinically characterized by aberrant elevated levels of glucose in the blood [1,2,3] The degree of this problem is exemplified in the fact that type 2 diabetes is becoming prevalent in children and adolescents [4,5]. An increased prevalence of type 2 diabetes is associated with increasing urbanization, ageing populations, increased sugar intake, obesity, and low fruit and vegetable consumption [7,8,9,10,11] Adequate management of this debilitating disease in many diabetic patients requires insulin treatment [12]. 14 classes of drugs are available to treat type 2 diabetes mellitus, but only

Methods

Discussion

Conclusion