Integrating synthesis, enzyme inhibition and in silico studies: Carbamoyl luteolin derivatives targeting Alzheimer's disease

Abstract Alzheimer's disease is one of the most common neurodegenerative disorders, where acetylcholinesterase (AChE) and monoacylglycerol lipase (MAGL) play critical roles in its pathophysiology. In this study, six carbamoyl luteolin derivatives were synthesized from luteolin via reactions with carbamoyl chloride reagents, achieving yields ranging from 41% to 64%. The structures of these derivatives were characterized using UV, HRMS, 1 H‐NMR, and 13 C‐NMR spectroscopy. Biological evaluation demonstrated that derivatives L1 (IC 50 = 42.0 μM for AChE, 58.0 μM for MAGL) and L3 (IC 50 = 114.2 μM for AChE, 34.9 μM for MAGL) exhibited significantly enhanced inhibitory activities compared with luteolin. Computational studies, including molecular docking and molecular dynamics simulations, validated the strong binding affinities and stable interactions of L1 and L3 with the enzymes' active sites. These findings suggest that modifying luteolin with carbamate groups can improve enzymatic inhibitory activity, providing a foundation for developing flavone‐based derivatives as potential therapeutic candidates for Alzheimer's disease.