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

Year: 2024

Type: article

Abstract: 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 ΔGbind 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 (ΔGbind) 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.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms252312803

Authors: Teresa Żołek, Rosa Purgatorio, Łukasz Kłopotowski, Marco Catto, Kinga Ostrowska

Institutions: Medical University of Warsaw, University of Bari Aldo Moro

Language: English

Topic: Cholinesterase and Neurodegenerative Diseases

Subfield: Pharmacology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,296