Flavonoid carbamate hybrids: design, synthesis, and evaluation as multi-target enzyme inhibitors for Alzheimer's disease†

Alzheimer's disease is characterized by cholinergic dysfunction and neuroinflammation, with acetylcholinesterase and monoacylglycerol lipase emerging as important therapeutic targets. In this study, a series of novel flavonoid carbamate derivatives were synthesized from chrysin and kaempferol, and their structures were confirmed via NMR and HRMS spectroscopy. The inhibitory activities of these compounds were evaluated against acetylcholinesterase and monoacylglycerol lipase using in vitro enzymatic assays. Among them, C3 and C5 exhibited significant dual inhibition, with IC₅₀ values of 22.86 μM and 46.65 μM for monoacylglycerol lipase, and 61.78 μM and 89.40 μM for acetylcholinesterase, respectively. Molecular docking studies revealed key binding interactions, while molecular dynamics simulations demonstrated their stability within the active sites of target enzymes. These findings highlight C3 and C5 as promising candidates for further investigation in the development of dual acetylcholinesterase/monoacylglycerol lipase inhibitors for Alzheimer's disease treatment.