Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2 H-benzo[ e][1,2]thiazin-2-yl]- N-arylacetamides: An In Silico and Biochemical Approach

Abstract

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-benzo[e][1,2]thiazin-2-yl)-N-arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c, 12a, 12d, 12e, and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC₅₀ values of 30.65, 18.25, 20.76, 35.14, and 24.24 μM, respectively, which were better than the standard drug, acarbose (IC₅₀ = 58.8 μM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.

Keywords: 1,2-Benzothiazines; anti-diabetic; molecular docking; synthesis; α-glucosidase inhibition.

Figure 1

Structures of biologically important 1,2-benzothiazine 1,1-dioxides.

Scheme 1

Synthesis of 1,2-benzothiazine-N-arylacetamides 11a–m and 12a–m.

Figure 2

Two-dimensional interaction modes of the most active compounds (11c, 12a, 12d, 12e, 12g) and the standard drug, acarbose. Blue color indicates ligand exposure and a green color dotted line indicates the interactions of receptor enzymes with ligands.

Figure 3

Three-dimensional interaction modes of the most active compounds (11c, 12a, 12d, 12e, 12g) and the standard drug, acarbose. Color portions show pocket selected and red portions indicate the ligand exposure points.