7-Hydroxy-4-Methylcoumarin Derivatives: A Multitargeted Ligand for the Management of Alzheimer's Disease

Alzheimer’s disease is a progressive neurodegenerative disorder marked by dementia, motor incoordination, cognitive decline, and respiratory depression. Its complex pathophysiology—characterized by hippocampal neuronal death, amyloid-β plaques, and neurofibrillary tangles—limits the development of disease-modifying therapies. This study explores 7-hydroxy-4-methylcoumarin derivatives as multitarget agents acting on acetylcholinesterase (AChE), β-secretase (BACE), and glycogen synthase kinase-3β (GSK-3β). Fifteen derivatives were designed via literature review and in-silico modeling. Docking studies identified MU-4, MU-5, MU-7, and MU-9 as promising candidates based on binding affinity and synthetic feasibility. FTIR confirmed successful synthesis. In-vitro AChE inhibition assays revealed MU-7 as a potent inhibitor, outperforming the standard. MU-4 and MU-7 showed antioxidant activity, though less than ascorbic acid. MU-9 demonstrated strong BACE selectivity and amyloid-inhibitory potential, increasing the viability of amyloid-β-induced cell lines to 83.58% at 25 μg/ml. MU-7 (secondary amine) is a potent AChE inhibitor, MU-4 (tertiary amine) exhibits antioxidant properties, and MU-9 (nitro-substituted) shows neuroprotective effects. These findings suggest that coumarin-based derivatives may offer both symptomatic relief and disease-modifying potential in Alzheimer’s therapy. Further studies are warranted to validate these results and advance drug development.