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dc.contributor.authorPISANI, Leonardo
dc.contributor.authorFarina, Roberta
dc.contributor.authorSoto-Otero, Ramón
dc.contributor.authorDENORA, Nunzio
dc.contributor.authorMangiatordi, Giuseppe Felice
dc.contributor.authorNicolotti, Orazio
dc.contributor.authorCATTO, Marco
dc.contributor.authorCarotti, Angelo
dc.date.accessioned2017-10-21T01:13:36Z
dc.date.available2017-10-21T01:13:36Z
dc.date.issued2016-03-17
dc.identifier.citationPisani, 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
dc.identifier.issn1420-3049
dc.identifier.urihttp://hdl.handle.net/10347/15952
dc.description.abstractThe 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
dc.language.isoeng
dc.publisherMDPI
dc.rights© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/)
dc.subjectAlzheimer’s disease
dc.subjectCholinesterase inhibitors
dc.subjectCoumarins
dc.subjectMAO inhibitors
dc.subjectMulti-target-directed ligands
dc.titleSearching 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
dc.typeinfo:eu-repo/semantics/article
dc.identifier.DOI10.3390/molecules21030362
dc.relation.publisherversionhttp://dx.doi.org/10.3390/molecules21030362
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.contributor.affiliationUniversidade de Santiago de Compostela. Departamento de Bioquímica e Bioloxía Molecular
dc.description.peerreviewedSI


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