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Molecules 2016, 21(3), 362; doi:10.3390/molecules21030362

Searching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif

1
Dipartimento di Farmacia—Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, via E. Orabona, 4, I-70125 Bari, Italy
2
Grupo de Neuroquimica, Departamento de Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Santiago de Compostela, San Francisco I, E-15782 Santiago de Compostela, Spain
*
Authors to whom correspondence should be addressed.
Academic Editors: Michael Decker and Diego Muñoz-Torrero
Received: 15 February 2016 / Revised: 5 March 2016 / Accepted: 10 March 2016 / Published: 17 March 2016
(This article belongs to the Special Issue Molecules against Alzheimer)
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Abstract

The need for developing real disease-modifying drugs against neurodegenerative syndromes, particularly Alzheimer’s disease (AD), shifted research towards reliable drug discovery strategies to unveil clinical candidates with higher therapeutic efficacy than single-targeting drugs. By following the multi-target approach, we designed and synthesized a novel class of dual acetylcholinesterase (AChE)-monoamine oxidase B (MAO-B) inhibitors through the decoration of the 2H-chromen-2-one skeleton. Compounds bearing a propargylamine moiety at position 3 displayed the highest in vitro inhibitory activities against MAO-B. Within this series, derivative 3h emerged as the most interesting hit compound, being a moderate AChE inhibitor (IC50 = 8.99 µM) and a potent and selective MAO-B inhibitor (IC50 = 2.8 nM). Preliminary studies in human neuroblastoma SH-SY5Y cell lines demonstrated its low cytotoxicity and disclosed a promising neuroprotective effect at low doses (0.1 µM) under oxidative stress conditions promoted by two mitochondrial toxins (oligomycin-A and rotenone). In a Madin-Darby canine kidney (MDCK)II-MDR1 cell-based transport study, Compound 3h was able to permeate the BBB-mimicking monolayer and did not result in a glycoprotein-p (P-gp) substrate, showing an efflux ratio = 0.96, close to that of diazepam. View Full-Text
Keywords: Alzheimer’s disease; cholinesterase inhibitors; coumarins; MAO inhibitors; multi-target-directed ligands Alzheimer’s disease; cholinesterase inhibitors; coumarins; MAO inhibitors; multi-target-directed ligands
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Pisani, L.; Farina, R.; Soto-Otero, R.; Denora, N.; Mangiatordi, G.F.; Nicolotti, O.; Mendez-Alvarez, E.; Altomare, C.D.; Catto, M.; Carotti, A. Searching for Multi-Targeting Neurotherapeutics against Alzheimer’s: Discovery of Potent AChE-MAO B Inhibitors through the Decoration of the 2H-Chromen-2-one Structural Motif. Molecules 2016, 21, 362.

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