Synthesis of Novel 2,3-Dihydro-1,5-Benzothiazepines as α-Glucosidase Inhibitors: In Vitro, In Vivo, Kinetic, SAR, Molecular Docking, and QSAR Studies

Abstract

In the present study, a series of 2,3-dihydro-1,5-benzothiazepine derivatives 1B-14B has been synthesized sand characterized by various spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using in vitro and in vivo mechanism-based assays. The tested compounds 1B-14B exhibited in vitro inhibitory potential against α-glucosidase with IC₅₀ = 2.62 ± 0.16 to 10.11 ± 0.32 μM as compared to the standard drug acarbose (IC₅₀ = 37.38 ± 1.37 μM). Kinetic studies of the most active derivatives 2B and 3B illustrated competitive inhibitions. Based on the α-glucosidase inhibitory effect, the compounds 2B, 3B, 6B, 7B, 12B, 13B, and 14B were chosen in vivo for further evaluation of antidiabetic activity in streptozotocin-induced diabetic Wistar rats. All these evaluated compounds demonstrated significant antidiabetic activity and were found to be nontoxic in nature. Moreover, the molecular docking study was performed to elucidate the binding interactions of most active analogues with the various sites of the α-glucosidase enzyme (PDB ID 3AJ7). Additionally, quantitative structure-activity relationship (QSAR) studies were performed based on the α-glucosidase inhibitory assay. The value of correlation coefficient (r) 0.9553 shows that there was a good correlation between the 1B-14B structures and selected properties. There is a correlation between the experimental and theoretical results. Thus, these novel compounds could serve as potential candidates to become leads for the development of new drugs provoking an anti-hyperglycemic effect.

Figure 1

Some reported drugs containing the thiazepine skeleton.

Figure 2

Structural representation of 2,3-dihydro-1,5-benzothiazepines.

Scheme 1. Synthesis of Chalcones 1C–14C and 2,3-Dihydro-1,5-Benzothiazepines 1B–14B

Figure 3

Effects of compounds on serum profile: (A) alkaline phosphatase (ALP), (B) serum glutamic pyruvic transaminase (SGPT), and (C) serum glutamic–oxaloacetic transaminase. All values are expressed as means ± SEM, n = 8. One-way ANOVA and Dunnett’s post hoc multiple comparison tests determine the values of P. ^!!!P < 0.001 as a comparison of the diabetic control group vs normal control, *P < 0.05, **P < 0.01 and ***P < 0.001 as a comparison of the diabetic control group vs test samples and glibenclamide-treated groups using one-way ANOVA followed by Dunnett’s comparison.

Figure 4

Kinetics of α-glucosidase inhibition by compound 2B: (a) Lineweaver–Burk plot in the absence and presence of different concentrations of compound 2B; (b) secondary plot between K_m and various concentrations of compound 2B.

Figure 5

Kinetics of α-glucosidase inhibition by compound 3B: (a) Lineweaver–Burk plot in the absence and presence of different concentrations of compound 3B; (b) secondary plot between K_m and various concentrations of compound 3B.

Figure 6

Structure–activity relationship of the synthesized target compounds 1B–14B.

Figure 7

Binding interactions of compounds (a) 2B and (b) 3B in the active site of α-glucosidase.