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

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.

A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes

“…Systematic exploration of the structural component of AM-2394 resulted in the identification of multiple compounds with improved solubility than AM-2394 (Kohn et al, 2016), with acceptable clearance and bioavailability in rat models. N-pyridin-2-yl benzamide analogs (62) were reported as allosteric activators of GK (Grewal, Kharb, et al, 2018;Grewal, Sharma, et al, 2018). The docking studies supported the binding of these analogs in the allosteric site of GK and they exhibited a significant reduction in blood glucose levels.…”

“…Kobayashi et al (2021) tested the toxicity of TMG123 as a GKA and reported that long-lasting hypoglycemia in rats is harmful to spermatogenesis and the testicular damage does not recover. A series of sulfamoyl benzamide derivatives as potential glucokinase (GK) activators were designed and synthesized by Grewal, Kharb, et al (2018)) and Grewal, Sharma, et al (2018) in vivo and in silico docking study of the synthesized compounds, revealed that compound 83 has a strong antidiabetic activity (Grewal, Kharb, et al, 2018;Grewal, Sharma, et al, 2018).…”

“…With all the understanding of disease management practices and prevention, the global community is still going to be overburdened with close to 592 million diabetes patients by 2035 (Dagogo-Jack, 2016). Although many oral drugs are available, monotherapy and combinatorial regimes have been found inadequate for sustainable control of blood glucose levels due to risks of hypoglycemia and toxic side effects (Fujieda et al, 2018;Grewal, Kharb, et al, 2018;Grewal, Sharma, et al, 2018). Therefore, research progress in the target identification and development of novel chemical entities for improved therapy has been accelerated.…”