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dc.creatorRoldán Peña, Jesús Migueles
dc.creatorRomero Real, V.es
dc.creatorHicke, Javieres
dc.creatorMaya Castilla, Inéses
dc.creatorFranconetti García, Antonioes
dc.creatorLagunes, Irenees
dc.creatorPadrón, José M.es
dc.creatorPetralla, Sabrinaes
dc.creatorPoeta, Eleonoraes
dc.creatorNaldi, Marinaes
dc.creatorBartolini, Manuelaes
dc.creatorMonti, Barbaraes
dc.creatorBolognesi, Maria L.es
dc.creatorLópez López, Óscares
dc.creatorFernández-Bolaños Guzmán, José Maríaes
dc.date.accessioned2024-02-05T17:04:02Z
dc.date.available2024-02-05T17:04:02Z
dc.date.issued2019-11-01
dc.identifier.citationRoldán Peña, J.M., Romero Real, V., Hicke, J., Maya Castilla, I., Franconetti García, A., Lagunes, I.,...,Fernández-Bolaños Guzmán, J.M. (2019). Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors. European Journal of Medicinal Chemistry, 181, 111550. https://doi.org/10.1016/j.ejmech.2019.07.053.
dc.identifier.issn0223-5234es
dc.identifier.issn1768-3254es
dc.identifier.urihttps://hdl.handle.net/11441/154623
dc.description.abstractConcerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aβ42, lacking neurotoxicity up to 5 μM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.es
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades CTQ2016-78703-Pes
dc.description.sponsorshipJunta de Andalucía FQM134es
dc.description.sponsorshipEuropean Union 501100008530es
dc.formatapplication/pdfes
dc.format.extent48 p.es
dc.language.isoenges
dc.publisherElsevieres
dc.relation.ispartofEuropean Journal of Medicinal Chemistry, 181, 111550.
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAlzheimer's diseasees
dc.subjectBuChEes
dc.subjectHeterodimerses
dc.subjectMultitargetes
dc.subjectTacrinees
dc.titleTacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitorses
dc.typeinfo:eu-repo/semantics/articlees
dc.type.versioninfo:eu-repo/semantics/acceptedVersiones
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses
dc.contributor.affiliationUniversidad de Sevilla. Departamento de Química orgánicaes
dc.relation.projectIDCTQ2016-78703-Pes
dc.relation.projectIDFQM134es
dc.relation.projectID501100008530es
dc.relation.publisherversionhttps://doi.org/10.1016/j.ejmech.2019.07.053es
dc.identifier.doi10.1016/j.ejmech.2019.07.053es
dc.journaltitleEuropean Journal of Medicinal Chemistryes
dc.publication.volumen181es
dc.publication.initialPage111550es
dc.contributor.funderMinisterio de Ciencia, Innovación y Universidades (MICINN). Españaes
dc.contributor.funderJunta de Andalucíaes
dc.contributor.funderEuropean Union (UE)es

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