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

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Dec 17

PMID 39684512

Authors

Teresa Zolek

Rosa Purgatorio

Lukasz Klopotowski

Marco Catto

Kinga Ostrowska

Affiliations

Soon will be listed here.

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

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