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

Abstract

In the present study, a series of 2,3-dihydro-1,5-benzothiazepine derivatives <b>1B</b>-<b>14B</b> has been synthesized sand characterized by various spectroscopic techniques. The enzyme inhibitory activities of the target analogues were assessed using <i>in vitro</i> and <i>in vivo</i> mechanism-based assays. The tested compounds <b>1B</b>-<b>14B</b> exhibited <i>in vitro</i> 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 <b>2B</b> and <b>3B</b> illustrated competitive inhibitions. Based on the α-glucosidase inhibitory effect, the compounds <b>2B</b>, <b>3B</b>, <b>6B</b>, <b>7B</b>, <b>12B</b>, <b>13B</b>, and <b>14B</b> were chosen <i>in vivo</i> 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 (<i>r</i>) 0.9553 shows that there was a good correlation between the <b>1B</b>-<b>14B</b> 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.