Design, Synthesis and Antidiabetic Activity of Novel Sulfamoyl Benzamide Derivatives as Glucokinase Activators

Viney Lather Viney Lather,Vikramjeet Singh Vikramjeet Singh,Ajmer Singh Grewal Ajmer Singh Grewal,Sukhbir Singh Sukhbir Singh,Deepti Pandita Deepti Pandita,Kapil Sharma Kapil Sharma

doi:10.15415/jptrm.2018.62008

Abstract

The present work has been planned to design, synthesize and evaluate the antidiabetic potential of a series of sulfamoyl benzamide derivatives as potential glucokinase (GK) activators. A new series of sulfamoyl benzamide derivatives was synthesized starting from 3-nitrobenzoic acid and characterized. In silico docking studies were performed to determine the binding interactions for the best fit conformations in the allosteric site of GK enzyme. Based on the results of in silico studies, the selected molecules were tested for their antidiabetic activity in animal studies (alloxan induced diabetic animal model). Compound 7 exhibited highest antidiabetic activity in animal studies. The results of in vivo antidiabetic activity studies were found to be in parallel to that of docking studies. These newly synthesized sulfamoyl benzamide derivatives thus can be treated as the initial hits for the development of novel, safe, effective and orally bioavailable GK activators as therapeutic agents for the treatment of type 2 diabetes.

Highlights

These newly synthesized sulfamoyl benzamide derivatives can be treated as the initial hits for the development of novel, safe, effective and orally bioavailable GK activators as therapeutic agents for the treatment of type 2 diabetes
Diabetes mellitus is a persistent metabolic disorder characterized by hyperglycemia with disturbed food metabolism, resulting from defect in either insulin action, insulin secretion or both, leading to vascular and tissue damage resulting in various other complications such as cataract, retinopathy, neuropathy, nephropathy, negative nitrogen balance, ketoacidosis, foot ulcers and cardiovascular disorders (Bastaki, 2005; Brownlee, 2001; Cade, 2008; Grewal et al, 2014)
The general scheme followed for synthesizing designed sulfamoyl benzamide derivatives is presented in Figure 2. 3-(Chlorosulphonyl)-5-nitrobenzoic acid was prepared by chlorosulphonation of 3-nitrobenzoic acid followed by refluxing with amines to obtain the sulphonamides

Summary

Introduction

Diabetes mellitus is a persistent metabolic disorder characterized by hyperglycemia with disturbed food metabolism, resulting from defect in either insulin action, insulin secretion or both, leading to vascular and tissue damage resulting in various other complications such as cataract, retinopathy, neuropathy, nephropathy, negative nitrogen balance, ketoacidosis, foot ulcers and cardiovascular disorders (Bastaki, 2005; Brownlee, 2001; Cade, 2008; Grewal et al, 2014). Type 2 diabetes (T2D) affecting more than 90% of all the diabetic patients, is a long-lasting malady of energy metabolism caused by reduced insulin action (Kohei et al, 2010; Olokoba et al, 2012). Even though a large number of options are available for the treatment of T2D, no single medicine is useful for achieving long lasting control of blood glucose levels in most of the T2D cases. Due to this reason, now-a-days physicians suggest treatment of T2D at an earlier stage with combination of antidiabetic agents. Overdose of antidiabetic drugs may cause severe hypoglycemia leading to severe toxic effects, and patients normally require urgent medical treatment (Olokoba et al, 2012). Results from several recent studies, including emerging clinical data, have demonstrated that smallmolecule glucokinase (GK) activators may be able to fill this void (Pal, 2009; Pal, 2009a; Grewal et al, 2014)

Methods

Results

Conclusion