New derivatives of paracetamol as potent α-glucosidase inhibitors: synthesis, in vitro, and in silico studies.

Twenty novel derivatives (4-24) of the commercially available drug paracetamol (1) 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 (2), which was further treated with hydrazine hydrate in absolute ethanol to get paracetamol hydrazide (3). Finally, various substituted aliphatic and aromatic aldehydes were refluxed with the hydrazide to get hydrazone-Schiff base derivatives (4-24). Structures of the synthesized derivatives were deduced through modern spectroscopic techniques (13C-,1H-NMR, and HR-ESI-MS). All the compounds were tested for α-glucosidase inhibitory potential because α-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 4 (IC50 = 90.98 ± 0.68 µM), 5 (IC50 = 78.12 ± 0.47 µM), 11 (IC50 = 27.54 ± 0.16 µM), 12 (IC50 = 83.52 ± 0.70 µM), and 13 (IC50 = 89.38 ± 0.67 µM) were found potent inhibitors of α-glucosidase as compared to the standard acarbose (IC50 = 873.34 ± 1.67 µM). In silico studies were conducted to evaluate the binding affinity of the synthesized compounds with the target enzyme.