Research ArticleDesign, synthesis and biological evaluation of novel thiazol-2-yl benzamide derivatives as glucokinase activators
Introduction
Diabetes mellitus, characterized by hyperglycaemia with disturbed food metabolism is a long-lasting disorder, and results from defect in either insulin secretion, insulin action or both (Bastaki, 2005). Diabetes causes tissue and vascular damage in body resulting in various other conditions including cataract, retinopathy, nephropathy, neuropathy, glycosuria, negative nitrogen balance, ketonaemia, ulcers and cardiovascular complication (Fowler, 2008; Saely et al., 2004; Cade, 2008). Diabetes is the main health problem with occurrence levels increasing to wide-ranging magnitudes and it is estimated that 366 million individuals will be diabetic by 2030 worldwide (Pal, 2009a). Diabetes mellitus is one of the leading causes of death across the globe, particularly in the developing world. Diabetes caused 5.1 million deaths in 2013, and every six seconds a person dies from diabetes. The latest figures from IDF Diabetes Atlas indicated diabetes as a major hurdle in the global development. Diabetes has become a global health burden, and has gained prime public health importance because of the complications associated with it (International Diabetes Federation, 2013; Olokoba et al., 2012). Type 1 diabetes mellitus consist of almost 5–10% of all diabetic patients and is characterised by gradual decrease in insulin secretion by pancreatic β-cells. In contrast, Type 2 diabetes mellitus (T2DM), which comprises of almost 90–95% of all diabetic patients, is a long-lasting malady of energy metabolism involving impaired glucose breakdown as well as reduced insulin action. Even though a large number of options are available for the treatment of diabetes, no single medicine is useful for achieving long lasting control of blood glucose levels in most of the diabetic cases. For that reason, these days most of the physicians recommend treatment with combination of antidiabetic agents at an earlier phase of the disorder (Alberti and Zimmet, 1998). Overdose of antidiabetic drugs may cause severe hypoglycaemia leading to severe toxic effects, and patients normally require urgent medical treatment. The scientific community is currently focusing on developing new, safe and clinically differentiated 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 small-molecule glucokinase (GK) activators may be able to fill this void (Pal, 2009b).
GK (ATP: D-glucose 6-phosphotransferase, EC 2.7.1.2), a cytoplasmic enzyme catalyses the phosphorylation of glucose to glucose-6-phosphate (G-6-P). GK demonstrates half-maximal activity at blood glucose concentration of roughly 8.0 mM. GK behaves as a molecular sensor for glucose-stimulated insulin release (GSIR) in pancreatic β-cells by linking blood glucose with secretion of insulin through complex signals. GK plays a major role in the regulation of glucose metabolism, thus GK is a potential target for the treatment of T2DM patients. GK is predominantly expressed in the pancreatic β-cells and hepatocytes in liver. In pancreas, it plays major role in regulating GSIR and in hepatocytes, it regulates the metabolism of glucose. GK also regulates the secretion of glucose dependent insulin tropic peptide and glucagon-like peptide-1 from entero-endocrine cells of the gut. In liver, GK attaches in the inactive state in the nucleus under the control of glucokinase regulatory protein. GK activators are the new class of drug candidates which act on GK enzyme and show their hypoglycaemic activity (Grewal et al., 2014).
A wide variety of molecules including benzamides (Pike et al., 2011; Li et al., 2011; Mao et al., 2012; Zhang et al., 2012a; Park et al., 2013, Park et al., 2014; Singh et al., 2017), acetamides (Cheruvallath et al., 2013; Pfefferkorn et al., 2012a), carboxamides (Pfefferkorn et al., 2012b), acrylamides (Sidduri et al., 2010), benzimidazoles (Ishikawa et al., 2009), quinazolines (Iino et al., 2009), thiazoles (Hinklin et al., 2013), pyrimidines (Filipski et al., 2013), and urea derivatives (Li et al., 2014; Zhang et al., 2012b) have been reported in last few years to act as potential GK activators. Despite the fact that several chemical moieties are being explored as GK activators by researchers, the maximum research efforts related to GK activators had mainly focused on the benzamide derivatives owing to their orientation and thus binding pattern in the allosteric site. The introduction of different functional groups at phenyl ring and amide −NH can result into wide range of molecules which can serve as the potential GK activators. Our group has recently reported some novel substituted benzamide derivatives as potential GK activators (Singh et al., 2017). Amongst these, compound having 4-phenylthiazole ring at amide −NH showed good antidiabetic potential in animal model (Fig. 1). In view of the critical importance of the GK activators in management of T2DM and the various research findings, we had made an attempt 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 targeted. Furthermore, the synthesized compounds were designed so as to be orally bioavailable by introducing groups like sulphonamide in the benzamide nucleus (Fig. 1).
Section snippets
Materials and methods
The chemicals were purchased from HiMedia Laboratories (Mumbai), SD Fine Chem. Ltd. (Mumbai), Otto Chem. Pvt. Ltd. (Mumbai), and Merck Millipore etc. and were used as such for the experiments. Melting points were calculated by using open capillary tubes on a Veego VMP-D melting point apparatus and are uncorrected. The reaction completion was monitored by thin layer chromatography (TLC) on silica gel plates (Silica Gel-G) and the purity of the compounds was ascertained by single spot on TLC
Chemistry
The general route followed for synthesizing thiazol-2-yl benzamide derivatives is presented in Scheme 1. Concisely, 3-(chlorosulphonyl)benzoic acid prepared by chlorosulphonation of 3-nitrobenzoic acid was refluxed with commercially available amines to obtain proposed sulphonamides. The benzoyl chlorides obtained by refluxing above products with thionyl chloride were further refluxed with thiazol-2-amines to synthesize the designed thiazol-2-yl benzamide derivatives. The final products were
Conclusion
Diabetes is the leading health problem with huge levels of occurrence globally. Despite the availability of several oral hypoglycaemic agents for the treatment of T2DM, it is one of the challenging areas for the researchers due to its complexity and involvement of not-so-clear therapeutic targets. GK enzyme has recently been identified as the key enzyme regulating the metabolism of glucose in liver and pancreas and thus serves as potential target for treatment of diabetes. The current study was
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
The authors are thankful to Management, JCD Vidyapeeth, Sirsa (Haryana) for their support and encouragement for this research work.
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2020, Journal of Molecular StructureCitation Excerpt :The amido nitrogen of benzamide nucleus was substituted with heterocyclic moieties in such a way that a strong hydrogen bonding and hydrophobic interactions with the amino acid residues in the allosteric site of 1V4S GK protein can be targeted. Heterocyclic ring structures such as thiazoles [9,11,19,20,22–25], indole [35,36], arylthiazole [25,29,37], pyrazole [8,11,20,21,28], 1,3,4-thiadiazole [4,26], pyrazin [21,34,38,39], and 1,2,4-thiadiazole [21,40] were selected based on the maximum GK activation observed during literature review to get good GK activation and favourable pharmacokinetics. Herein, we report the design and synthesis of N-(heterosubstituted)-2-(substituted-sulfonamido)benzamide derivatives as a promising preclinical candidate for the treatment of T2DM.