Synthesis and α-Glucosidase Inhibition Activity of 2-[3-(Benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2H-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.

Recent Advances in Synthesis and Medicinal Evaluation of 1,2‐Benzothiazine Analogues

“…[146] Their low IC 50 values proved them to be even better than the reference drug acarbose (IC 50 = 38. The same research group carried out the further expansion of research work, [74] to identify compounds 136 a-m and 137 am as potential targets which are synthesized by treating 22 a-b with 2-bromo-N-arylacetamides 135 a-m in presence of potassium carbonate in DMF (Scheme 20).…”

“…The remarkable features of these heterocycles can be witnessed by their large number of publications (1782) and citations (11592) in recent times. Here in this review, therapeutic applications of 1,2‐benzothiazines in the arena of anti‐inflammatory, [23–37] anticancer, [38–56] antimicrobial, [57–62] antioxidant, [56,58,63–66] antidiabetic, [67–74] nor‐A efflux pump inhibitor, [75] antiepileptic, [76] anti‐arthritis, [77] anti‐HIV‐1, [78–81] alkaline phosphate inhibitors, [82] anti‐monoamine oxidase, [83] anti‐11β‐hydroxysteroid dehydrogenase, [84–85] calpain‐1 inhibitors, [86–87] and hepatitis virus‐C [88–89] along with their corresponding synthesis have been visualized. The prominence attained by derivatives of thiazole [90–91] and thiazine [15,92] lead researchers to construct medications like alpelisib and prochlorperazine maleate and a lot more (Figure 1).…”

Synthesis of γ‐Butyrolactone Derivatives from Dihydrotagetone and Evaluation of Their Antidiabetic Activity

“…The clinically available oral AGI drugs, acarbose, miglitol, and voglibose are therapeutic approaches to reduce the risk of T2DM. [6] These AGIs are associated with gastrointestinal adverse effects like stomach pain, diarrhoea, cramping, enhanced flatulence, and rectal bleeding. [7,8] The adverse effects of these drugs are forcing researchers to search a new, effective, and safer alternate molecules.…”

“…Thus, the identification of α ‐glucosidase inhibitors (AGIs) has sparked a lot of interest. The clinically available oral AGI drugs, acarbose, miglitol, and voglibose are therapeutic approaches to reduce the risk of T2DM [6] . These AGIs are associated with gastrointestinal adverse effects like stomach pain, diarrhoea, cramping, enhanced flatulence, and rectal bleeding [7,8] .…”

Discovery of Amide-Functionalized Benzimidazolium Salts as Potent α-Glucosidase Inhibitors

“…Over the recent years, heterocyclic compounds have been extensively studied as α-glucosidase inhibitors [ 26 , 27 , 28 ]. More specifically, the benzimidazole ring system has emerged as an efficient template for new and potential anti-diabetic agents [ 29 , 30 , 31 ].…”