Abstract
Current research is based on the identification of novel inhibitors of α-amylase enzyme. For that purpose, new hybrid molecules of hydrazinyl thiazole substituted chromones 5–27 were synthesized by multi-step reaction and fully characterized by various spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemistry of the iminic bond was confirmed by NOESY analysis of a representative molecule. All compounds 5–27 along with their intervening intermediates 1–4, were screened for in vitro α-amylase inhibitory, DPPH and ABTS radical scavenging activities. All compounds showed good inhibition potential in the range of IC50 = 2.186–3.405 µM as compared to standard acarbose having IC50 value of 1.9 ± 0.07 µM. It is worth mentioning that compounds were also demonstrated good DPPH (IC50 = 0.09–2.233 µM) and ABTS (IC50 = 0.584–3.738 µM) radical scavenging activities as compared to standard ascorbic acid having IC50 = 0.33 ± 0.18 µM for DPPH and IC50 = 0.53 ± 0.3 µM for ABTS radical scavenging activities. In addition to that cytotoxicity of the compounds were checked on NIH-3T3 mouse fibroblast cell line and found to be non-toxic. In silico studies were performed to rationalize the binding mode of compounds (ligands) with the active site of α-amylase enzyme.
Highlights
Diabetes mellitus (DM) is a metabolic disorder caused by the insufficient insulin secretion and decreased insulin activity which leads to the disruption of carbohydrate, protein, and fat metabolism[1]
Treatment of type-II DM includes a number of therapeutic approaches such as stimulation of the endogenous insulin secretion, reduction of insulin’s demand, and inhibition of carbohydrate degradation[3]
We have reported 3-thiazolyl coumarin as potent inhibitors of α-glucosidase enzyme[32]
Summary
Diabetes mellitus (DM) is a metabolic disorder caused by the insufficient insulin secretion and decreased insulin activity which leads to the disruption of carbohydrate, protein, and fat metabolism[1]. One of therapeutic strategies is to reduce the post-prandial glucose levels by retarding the absorption of glucose This could possibly be done by the inhibition of enzymes, α-glucosidase and α-amylase, those are responsible to hydrolyze oligosaccharides and disaccharides into monosaccharides[1,4,5,6]. Inhibitors of α-amylase enzyme such as acarbose, function by delaying the carbohydrate digestion and cause a decreased rate of glucose absorption and diminishing the postprandial plasma glucose level[9,10]. Chromone or 4H-chromen-4-one is a naturally occurring heterocycle based on benzopyrone scaffold and widely distributed in nature mainly in plants. It is the core fragment of several flavonoids e.g. flavones and isoflavones. Our research group has identified many lead scaffolds having antiglycation and α-glucosidase inhibitory activities (Fig. 1), as a possible treatment for diabetic management[26,27,28,29,30,31]
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