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-2<i>H</i>-benzo[<i>e</i>][1,2]thiazin-2-yl)-<i>N</i>-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, <i>N</i>-(4-bromophenyl)-2-(4-hydroxy-3-(3-methoxybenzoyl)-1,1-dioxido-2<i>H</i>-benzo[e][1,2]thiazin-2-yl)acetamide (<b>12i</b>), 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 <b>12i</b> in complex with α-amylase also showed that the compound is binding in a fashion similar to that predicted by molecular docking studies.