Derivatization, molecular docking and <i>in vitro</i> acetylcholinesterase inhibitory activity of glycyrrhizin as a selective anti-Alzheimer agent

Abstract

Acetylcholinesterase inhibitors (AChE-Is) increase both level and duration of action of acetylcholine (ACh); thus, alleviate symptoms of Alzheimer's disease (AD). Glycyrrhizin, is the main active compound in liquorice root. Its aglycone, glycyrrhetinic acid, has shown several beneficial pharmacological activities. This study reports the synthesis and screening of a series of glycyrrhetinic acid analogs as AChE-Is. Fourteen derivatives were prepared, of which five derivatives are recorded as new viz., 3-phenyl-carbamoyl-18β-glycyrrhetinic acid (<b>J9</b>), 3-acetyl-18β-glycyrrhetinic-30-anilinamide (<b>J10</b>), 3-acetyl-18β-glycyrrhetinic-30-ethanolamide (<b>J11</b>), 3-acetyl-18β-glycyrrhetinic-30-<i>n</i>-butylamide (<b>J12</b>) and 18β-glycyrrhetinic acid-30-prenyl ester (<b>J14</b>), in addition to nine known derivatives (<b>J1</b>-<b>J8</b> & <b>J13</b>). Compounds <b>J12, J11, J0</b> and <b>J3</b> showed remarkable AChE-I activity with IC₅₀ values of 3.43, 5.39, 6.27 and 8.68 μM, respectively. These results are in full agreement with the docking study. The active compounds were non-cytotoxic to normal cells (WI-38).