Development of coumarin-based acetylcholinesterase inhibitors: Synthesis, biological assessment and computational simulations

Abstract

Novel coumarin-based derivatives ( 5 , 6a-c and 10a-j ) have been designed, synthesized and biologically assessed as multimodal anti-Alzheimer agents targeting acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and glycogen synthase kinase-3β (GSK-3β). The synthesized derivatives have been afforded in a good yield and the structures confirmed by the spectral analysis. Among these derivatives, four derivatives ( 10c , 10d , 10 f and 10i ) exhibited remarkable inhibitory activity against the acetylcholinesterase enzyme in nanomolar concentration (IC50 = 5.93 ± 0.06, 3.97 ± 0.15, 3 ± 0.1, and 4.97 ± 0.06 nM, respectively), surpassing the reference donepezil drug (IC50 = 7.03 ± 0.15 nM). Moreover, derivative 10 f demonstrated a significant BuChE inhibitory activity (IC50 = 303 ± 0.03 nM), about 2-fold the donepezil activity. Consequently, derivative 10 f was selected for the GSK-3β inhibition assay and displayed a greater inhibitory activity in nanomolar range (7.58 ± 0.83 nM) than the reference broad-spectrum kinase inhibitor staurosporine (8.63 ± 0.94 nM). Additionally, derivative 10 f was assayed for the iron chelating capacity and showed significant activity compared to the iron chelator EDTA. The molecular docking of derivatives 10c , 10d , 10 f , and 10i utilizing the AChE enzyme as a target protein (PDB: 4EY7 ) was evaluated and highlighted 10 f as a promising lead candidate with favorable interactions and high affinity. The key hydrogen bonds, hydrophobic contacts, and π–π stacking interactions support the observed bioactivity. Furthermore, molecular dynamics simulations indicated the stability of the compound–enzyme complexes, with low RMSD fluctuations and favorable binding free energies. Collectively, these findings emerge as derivative 10 f , a promising lead scaffold for Alzheimer's disease with multimodal activity.