Zolek_2024_Int.J.Mol.Sci_25_

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 O-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 deltaG(bind) estimation, two series of derivatives emerged as potent MTDLs: 8-acetyl-7-hydroxy-4-methylcoumarin (IC(50): 1.52-4.95 microM for hAChE, 6.97-7.65 microM for hMAO-A) and 4,7-dimethyl-5-hydroxycoumarin (IC(50): 1.88-4.76 microM for hMAO-B). They displayed binding free energy (deltaG(bind)) of -76.32 kcal/mol (11) and -70.12 kcal/mol (12) against AChE and -66.27 kcal/mol (11) and -62.89 kcal/mol (12) against MAO-A. It is noteworthy that compounds 11 and 12 demonstrated efficient binding to both AChE and MAO-A, while compounds 3 and 10 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.