J. Pharm. Technol. Res. Manag.

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

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

KEYWORDS

Antidiabetic activity, Benzamides, Diabetes mellitus, Glucokinase, GK activators, Molecular Docking

PUBLISHED DATE Nov. 2, 2018
PUBLISHER The Author(s) 2018. This article is published with open access at www.chitkara.edu.in/publications.
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.

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). The scientific community is currently focusing on developing new, safe and clinically different antidiabetic agents that can be used as mono drug therapy with improved efficacy. 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).

GK is a cytoplasmic enzyme which catalyzes the conversion of glucose to glucose-6-phosphate in presence of ATP and controls the blood glucose levels in a safe and narrow physiological range in humans. GK is predominantly expressed in the pancreatic β-cells and hepatocytes in liver (Matschinsky and Porte, 2010; Grewal et al., 2014). In pancreatic β-cells, it plays chief role by regulating glucosestimulated insulin release and in liver hepatocytes cells, it regulates the sugar metabolism. GK is an emerging target for the therapeutic management of T2D patients as it plays a key function in the regulation of carbohydrate breakdown. GK activators are the new class of drug candidates which act on GK enzyme and show their hypoglycemic activity (Coghlan and Leighton, 2008; Pal, 2009; Perseghin, 2010; Matschinsky et al., 2011). A broad diversity of chemical entities including benzamide derivatives (Iino et al., 2010; Pike et al., 2011; Li et al., 2011; Mao et al., 2012; Zhang et al., 2012; Park et al., 2013; Park et al., 2014; Singh et al., 2016; Tsumura et al., 2017; Wang et al., 2017; Charaya et al., 2018), acetamides (Mitsuya et al., 2009; Pfefferkorn et al., 2012; Cheruvallath et al., 2013), carboxamides (Li et al., 2010; Pfefferkorn et al., 2012a; Ye et al., 2012), acrylamides (Sidduri et al., 2010), benzimidazoles (Ishikawa et al., 2009; Takahashi et al., 2009), quinazolines (Iino et al., 2009), thiazoles (Hinklin et al., 2013), pyrimidines (Filipski et al., 2013), and urea derivatives (Zhang et al., 2012a; Li et al., 2014) have been reported in last few years to act as potent GK activators. The maximum research efforts related to GK activators had mainly focused on the benzamide derivatives owing to their orientation and binding pattern in the allosteric binding site of the GK protein (Grewal et al., 2014). In view of the critical importance of the GK activators in management of T2D and the potential of benzamide derivatives as GK activators, we planned to design and synthesize some novel GK activators based on benzamide nucleus. The substitutions on benzamide nucleus were carried out in such a way that strong H-bond and hydrophobic interactions with residues in the allosteric site of GK protein can be achieved

Page(s) 113-122
URL http://dspace.chitkara.edu.in/jspui/handle/123456789/789
ISSN Print : 2321-2217, Online : 2321-2225
DOI 10.15415/jptrm.2018.62008
CONCLUSION

A new series of sulfamoyl benzamide derivatives were designed based on the pharmacophoric features required for binding of GK activators with GK by means of substitution at amide linker and addition of sulphonamide moieties at the aromatic ring. Amongst the several synthesized derivatives, compounds 2, 6,7, 8 and 10 showed good interactions with the residues in the allosteric binding site GK protein in molecular docking studies. Amongst, the selected compounds tested in vivo, compound 7 displayed greater antihyperglycemic efficacy in antidiabetic studies. The results of the in vivo antidiabetic assay were in accordance to that of in silico molecular docking studies. The molecular properties of these newer benzamide derivatives were also found to follow the Lipinski’s rule of five for drug-like property. These synthesized molecules can behave as the early hit molecules for further development of safe, potent and oral GK activators for the potential treatment of diabetic disorders.

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