Coumarin Derivative Hybrids: Novel Dual Inhibitors Targeting Acetylcholinesterase and Monoamine Oxidases for Alzheimer’s Therapy

Multi-target-directed ligands (MTDLs) represent a promising frontier in tackling the complexity of multifactorial pathologies like Alzheimer's disease (AD). The synergistic inhibition of MAO-B, MAO-A, and AChE is believed to enhance treatment efficacy. A novel coumarin-based molecule substituted with <i>O</i>-phenylpiperazine via three- and four-carbon linkers at the 5- and 7-positions, has been identified as an effective MTDL against AD. Employing a medicinal chemistry approach, combined with molecular docking, molecular dynamic simulation, and ΔG_bind estimation, two series of derivatives emerged as potent MTDLs: 8-acetyl-7-hydroxy-4-methylcoumarin (IC₅₀: 1.52-4.95 μM for hAChE, 6.97-7.65 μM for hMAO-A) and 4,7-dimethyl-5-hydroxycoumarin (IC₅₀: 1.88-4.76 μM for hMAO-B). They displayed binding free energy (ΔG_bind) of -76.32 kcal/mol (<b>11</b>) and -70.12 kcal/mol (<b>12</b>) against AChE and -66.27 kcal/mol (<b>11</b>) and -62.89 kcal/mol (<b>12</b>) against MAO-A. It is noteworthy that compounds <b>11</b> and <b>12</b> demonstrated efficient binding to both AChE and MAO-A, while compounds <b>3</b> and <b>10</b> significantly reduced MAO-B and AChE aggregation in vitro. These findings provide structural templates for the development of dual MAO and AChE inhibitors for the treatment of neurodegenerative diseases.