New derivatives of paracetamol as potent <i>α</i>-glucosidase inhibitors: synthesis, <i>in vitro,</i> and <i>in silico</i> studies

Twenty novel derivatives (<b>4</b>–<b>24</b>) of the commercially available drug paracetamol (<b>1</b>) were synthesized in decent yields by refluxing ethyl chloroacetate with paracetamol in the presence of potassium carbonate in DMF solvent to obtain ethyl 2-(4-acetamidophenoxy)acetate (<b>2</b>), which was further treated with hydrazine hydrate in absolute ethanol to get paracetamol hydrazide (<b>3</b>). Finally, various substituted aliphatic and aromatic aldehydes were refluxed with the hydrazide to get hydrazone-Schiff base derivatives (<b>4–24</b>). Structures of the synthesized derivatives were deduced through modern spectroscopic techniques (¹³C-,¹H-NMR, and HR-ESI-MS). All the compounds were tested for <i>α</i>-glucosidase inhibitory potential because <i>α</i>-glucosidase inhibitors slow down carbohydrate digestion thus normalize blood glucose level indicates a promising target for the treatment of diabetes. Among them, five compounds including <b>4</b> (IC₅₀ = 90.98 ± 0.68 µM), <b>5</b> (IC₅₀ = 78.12 ± 0.47 µM), <b>11</b> (IC₅₀ = 27.54 ± 0.16 µM), <b>12</b> (IC₅₀ = 83.52 ± 0.70 µM), and <b>13</b> (IC₅₀ = 89.38 ± 0.67 µM) were found potent inhibitors of <i>α</i>-glucosidase as compared to the standard acarbose (IC₅₀ = 873.34 ± 1.67 µM). <i>In silico</i> studies were conducted to evaluate the binding affinity of the synthesized compounds with the target enzyme.