Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors

Concerned 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 o...

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Authors: Roldán Peña, Jesús Miguel, Romero Real, V., Hicke, Javier, Maya Castilla, Inés, Franconetti García, Antonio, Lagunes, Irene, Padrón, José M., Petralla, Sabrina, Poeta, Eleonora, Naldi, Marina, Bartolini, Manuela, Monti, Barbara, Bolognesi, Maria L., López López, Óscar, Fernández-Bolaños Guzmán, José María
Format: article
Status:Versión aceptada para publicación
Publication Date:2019
Country:España
Institution:Universidad de Sevilla (US)
Repository:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/154623
Online Access:https://hdl.handle.net/11441/154623
https://doi.org/10.1016/j.ejmech.2019.07.053
Access Level:Open access
Keyword:Alzheimer's disease
BuChE
Heterodimers
Multitarget
Tacrine
id ES_e6eb59b9dad508ff85aeecff9830f856
oai_identifier_str oai:idus.us.es:11441/154623
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spelling Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitorsRoldán Peña, Jesús MiguelRomero Real, V.Hicke, JavierMaya Castilla, InésFranconetti García, AntonioLagunes, IrenePadrón, José M.Petralla, SabrinaPoeta, EleonoraNaldi, MarinaBartolini, ManuelaMonti, BarbaraBolognesi, Maria L.López López, ÓscarFernández-Bolaños Guzmán, José MaríaAlzheimer's diseaseBuChEHeterodimersMultitargetTacrineConcerned 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.Ministerio de Ciencia, Innovación y Universidades CTQ2016-78703-PJunta de Andalucía FQM134European Union 501100008530ElsevierQuímica OrgánicaMinisterio de Ciencia, Innovación y Universidades (MICINN). EspañaJunta de AndalucíaEuropean Union (UE)2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/154623https://doi.org/10.1016/j.ejmech.2019.07.053reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésEuropean Journal of Medicinal Chemistry, 181, 111550.CTQ2016-78703-PFQM134501100008530https://doi.org/10.1016/j.ejmech.2019.07.053info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1546232026-06-17T12:51:07Z
dc.title.none.fl_str_mv Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
title Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
spellingShingle Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
Roldán Peña, Jesús Miguel
Alzheimer's disease
BuChE
Heterodimers
Multitarget
Tacrine
title_short Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
title_full Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
title_fullStr Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
title_full_unstemmed Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
title_sort Tacrine-O-protected phenolics heterodimers as multitarget-directed ligands against Alzheimer's disease: Selective subnanomolar BuChE inhibitors
dc.creator.none.fl_str_mv Roldán Peña, Jesús Miguel
Romero Real, V.
Hicke, Javier
Maya Castilla, Inés
Franconetti García, Antonio
Lagunes, Irene
Padrón, José M.
Petralla, Sabrina
Poeta, Eleonora
Naldi, Marina
Bartolini, Manuela
Monti, Barbara
Bolognesi, Maria L.
López López, Óscar
Fernández-Bolaños Guzmán, José María
author Roldán Peña, Jesús Miguel
author_facet Roldán Peña, Jesús Miguel
Romero Real, V.
Hicke, Javier
Maya Castilla, Inés
Franconetti García, Antonio
Lagunes, Irene
Padrón, José M.
Petralla, Sabrina
Poeta, Eleonora
Naldi, Marina
Bartolini, Manuela
Monti, Barbara
Bolognesi, Maria L.
López López, Óscar
Fernández-Bolaños Guzmán, José María
author_role author
author2 Romero Real, V.
Hicke, Javier
Maya Castilla, Inés
Franconetti García, Antonio
Lagunes, Irene
Padrón, José M.
Petralla, Sabrina
Poeta, Eleonora
Naldi, Marina
Bartolini, Manuela
Monti, Barbara
Bolognesi, Maria L.
López López, Óscar
Fernández-Bolaños Guzmán, José María
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Química Orgánica
Ministerio de Ciencia, Innovación y Universidades (MICINN). España
Junta de Andalucía
European Union (UE)
dc.subject.none.fl_str_mv Alzheimer's disease
BuChE
Heterodimers
Multitarget
Tacrine
topic Alzheimer's disease
BuChE
Heterodimers
Multitarget
Tacrine
description Concerned 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/154623
https://doi.org/10.1016/j.ejmech.2019.07.053
url https://hdl.handle.net/11441/154623
https://doi.org/10.1016/j.ejmech.2019.07.053
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv European Journal of Medicinal Chemistry, 181, 111550.
CTQ2016-78703-P
FQM134
501100008530
https://doi.org/10.1016/j.ejmech.2019.07.053
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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