A novel library of -arylketones as potential inhibitors of α-glucosidase: Their design, synthesis, in vitro and in vivo studies

Abstract

α-glucosidase is an essential enzyme located at the brush border of intestines. It is an important therapeutic target for type II diabetes. Herein we have designed a library of novel α-arylketones as inhibitors of α-glucosidase (yeast origin) via scaffold hopping and bioisosteric modification of known inhibitors of α-glucosidase. The design was validated through molecular docking that revealed strong binding interactions of the newly designed compounds against α-glucosidase. A library comprising of 15 compounds was synthesized in a combinatorial fashion, where the advanced amide intermediates were accessed through “shot gun” synthesis. The final compounds were characterized by 1H, 13C-NMR and with high resolution mass spectroscopy. In vitro screening of the compounds against yeast α-glucosidase revealed substantial inhibition with IC50s in the range of 4–10 μM (the standard drug acarbose inhibits α-glucosidase with an IC50 of 9.95 μM). Reaction kinetics suggested mixed type inhibition. Finally, in vivo studies of the most active compound 3c against Streptozotocin induced male albino Wistar rats revealed that its administration in the rats for about 4 weeks lead to a highly significant (P < 0.001) decrease in the fasting blood glucose (FBG) compared to the untreated diabetic rats. Moreover, lower dose of 3c had better control over FBG in contrast to high-dose.

Perilla frutescens Leaf Extract and Fractions: Polyphenol Composition, Antioxidant, Enzymes (α-Glucosidase, Acetylcholinesterase, and Tyrosinase) Inhibitory, Anticancer, and Antidiabetic Activities

“…It is believed that α-glucosidase, acetylcholinesterase (AChE), and tyrosinase are important metabolic enzymes relating with oxidative stress, and they are shown to be the key targets of T2DM, Alzheimer’s disease (AD), mammalian melanogenesis, and fruit or vegetable enzymatic browning, respectively [ 30 , 31 , 32 ]. Natural food and medicinal plants are excellent resources of α-glucosidase, AChE, and tyrosinase inhibitors, and have the potential to be novel strategies for the prevention and treatment of these diseases or hazards [ 32 , 33 , 34 ].…”

Lactobacillus Sps in Reducing the Risk of Diabetes in High-Fat Diet-Induced Diabetic Mice by Modulating the Gut Microbiome and Inhibiting Key Digestive Enzymes Associated with Diabetes

“…In current medical practice, α-amylase and α-GLU are essential targets for T2D and their inhibitors are used as drugs to alleviate the disease. By delaying the absorption of carbohydrates from the small intestine, blood glucose level is controlled, so is the progression of T2D [ 51 ].…”

α‐Glucosidase inhibitors screening from Cyclocarya paliurus based on spectrum–effect relationship and UPLC–MS/MS

“…The incidence of DM is rising globally, and there will be nearly 600 million diabetics in the world by 2035 according to the prediction of the International Diabetes Federation (Whiting et al, 2011). α ‐Glucosidase, located in the brush border of the small intestine, can disintegrate oligosaccharides and disaccharides into monosaccharides (Luthra et al, 2017). The α ‐glucosidase inhibitors can competitively combine with α ‐glucosidase to inhibit the hydrolysis of oligosaccharides and disaccharides, which can reduce postprandial hyperglycemia, thus keeping blood glucose levels at normal levels (Zhang et al, 2017).…”