Current advances in 7-hydroxycoumarin derivatives as potential therapeutic agents for Alzheimer's disease

Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, remains a major cause of cognitive decline in the aging population. Current pharmacological interventions provide only symptomatic relief, highlighting the urgent need for novel therapeutic strategies capable of modifying disease progression. Coumarins, particularly 7-hydroxycoumarin and its synthetic derivatives, have attracted considerable interest due to their broad pharmacological potential, including cholinesterase inhibition, monoamine oxidase (MAO) inhibition, antioxidant, anti-amyloidogenic and metal-chelating activities. This review presents a comprehensive analysis of synthetic 7-hydroxycoumarin derivatives reported over the past 15 years as potential anti-Alzheimer agents, classifying them according to their actions on key pathological hallmarks of AD, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), MAO-B, β-amyloid (Aβ) aggregation, oxidative stress and neuroinflammation. Structure-activity relationship (SAR) analysis reveals that substitutions at the 7-, 3- and 4-positions of the coumarin scaffold critically influence pharmacological potency and selectivity, with aromatic and alkyl amine substitutions generally enhancing enzyme inhibition and neuroprotective effects. Several derivatives exhibited sub-micromolar to nanomolar inhibitory activity against AChE and MAO-B, along with antioxidant and anti-Aβ aggregation properties, supporting their multifunctional behaviour. Overall, this review highlights the therapeutic promise of 7-hydroxycoumarin derivatives as multitarget-directed ligands (MTDLs) and provides valuable insights for the rational design of new lead compounds for Alzheimer's disease.