Identification of Cyclic Sulfonamides with an N-Arylacetamide Group as α-Glucosidase and α-Amylase Inhibitors: Biological Evaluation and Molecular Modeling

Abstract

Diabetes mellitus (DM), a complicated metabolic disorder, is due to insensitivity to insulin function or reduction in insulin secretion, which results in postprandial hyperglycemia. α-Glucosidase inhibitors (AGIs) and α-amylase inhibitors (AAIs) block the function of digestive enzymes, which delays the carbohydrate hydrolysis process and ultimately helps to control the postprandial hyperglycemia. Diversified 2-(3-(3-methoxybenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides were synthesized and evaluated for their in vitro inhibitory potential against α-glucosidase and α-amylase enzymes. The compounds with chloro, bromo and methyl substituents demonstrated good inhibition of α-glucosidase enzymes having IC50 values in the range of 25.88–46.25 μM, which are less than the standard drug, acarbose (IC50 = 58.8 μM). Similarly, some derivatives having chloro, bromo and nitro substituents were observed potent inhibitors of α-amylase enzyme, with IC50 values of 7.52 to 15.06 μM, lower than acarbose (IC50 = 17.0 μM). In addition, the most potent compound, N-(4-bromophenyl)-2-(4-hydroxy-3-(3-methoxybenzoyl)-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)acetamide (12i), was found to be a non-competitive and competitive inhibitor of α-glucosidase and α-amylase enzymes, respectively, during kinetic studies. The molecular docking studies provided the binding modes of active compounds and the molecular dynamics simulation studies of compound 12i in complex with α-amylase also showed that the compound is binding in a fashion similar to that predicted by molecular docking studies.

Fragment-Based Dynamic Combinatorial Chemistry for Identification of Selective α-Glucosidase Inhibitors

“…The resulting oligosaccharides are further hydrolyzed into absorbable α- d -glucose by α-glucosidase (EC 3.2.1.20) located at the intestine’s brush boundary, leading to an increase in blood sugar level (Figure ). − Thus, inhibition on either of these enzymes can be a solution to blood sugar regulation. Indeed, acarbose, miglitol and voglibose are clinically prescribed α-amylase and α-glucosidase inhibitors for the treatment of T2DM. , However, serious side effects such as diarrhea, gastrointestinal distress, and abdominal distension are often reported during the application of those medicines. , Several enzymatic studies have documented that α-amylase inhibition is one of the leading causes for gastrointestinal side effects, as it can also facilitate the transfer of undigested polysaccharides to the intestine .…”

Inhibition Kinetics and Theoretical Studies on Zanthoxylum chalybeum Engl. Dual Inhibitors of α-Glucosidase and α-Amylase

“…In previously reported in silico studies, a number of 1,2-benzothiazine and xanthone derivatives, 8-c-ascorbyl(-)-epigallocatechin, and Voglibose also showed α-glucosidase inhibition through interaction with Asp203, Asp542, and Arg526 pocket residues of the receptor protein [ 47 , 48 , 49 , 50 ]. Additionally, reported molecular docking studies of 1, 2-benzothiazine derivative against α-amylase indicated excellent binding affinities with the residues TRP83, ASP340, ARG 204, and GLU 230 [ 51 ].…”

Design, Synthesis and Pharmacological Evaluation of 2-(3-BenzoyI-4-Hydroxy-1,1-Dioxido-2H-Benzo[e][1,2]thiazin-2-yI)-N-(2-Bromophenyl) Acetamide as Antidiabetic Agent

“…The selected compound (Figure 1), 2-(3-benzoyl-4-hydroxy-1,1-dioxido-2H-benzo[e] [1,2]thiazin-2-yl)-1-(2-bromophenyl) acetamide (FA2) was synthesized by reported methodology (Scheme 1). 30 The 3-benzoyl-4-hydroxy-1,2-benzothiazine 1,1-dioxide (0.5 g, 1.66 mmoles), 2-bromo-N-(2-bromophenyl) acetamide (0.49 g, 1.67 mmoles) and K2CO3 (0.46 g, 2.33 mmoles) were mixed in dimethyl formamide (10 mL). The reaction mixture was vortex for 10 minutes at 28-30 °C, then heated at 100 °C for 120 minutes.…”