Carbamoyl flavonoids as dual inhibitors of acetylcholinesterase and monoacylglycerol lipase: synthesis, in vitro evaluation, and computational studies

Alzheimer’s disease is a complex neurodegenerative disorder characterized by cognitive decline and memory loss, with acetylcholinesterase and monoacylglycerol lipase being two key enzymes involved in its pathogenesis. In this study, a series of carbamoyl flavonoid derivatives were synthesized and evaluated as potential dual inhibitors of acetylcholinesterase and monoacylglycerol lipase. Among them, compound B3 (a baicalein derivative) exhibited the most potent dual inhibition, with IC₅₀ values of 67.95 µM for acetylcholinesterase and 61.28 µM for monoacylglycerol lipase. Molecular docking and molecular dynamics simulations confirmed the strong binding affinity and stability of B3 within the active sites of both enzymes. The MM-GBSA binding free energy analysis revealed ΔG_bind values of –31.58 ± 2.24 kcal/mol for acetylcholinesterase and –41.24 ± 2.42 kcal/mol for monoacylglycerol lipase, indicating favorable interactions through hydrogen bonding, π-stacking interactions, and hydrophobic contacts. These findings suggest that carbamoyl flavonoid derivatives, particularly B3, hold promise as multifunctional inhibitors, providing a novel and effective strategy for the treatment of Alzheimer’s disease.