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http://hdl.handle.net/2445/59194
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DC Field | Value | Language |
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dc.contributor.author | Di Pietro, O. | - |
dc.contributor.author | Pérez Areales, Francisco Javier | - |
dc.contributor.author | Juárez-Jiménez, Jordi | - |
dc.contributor.author | Espargaró Colomé, Alba | - |
dc.contributor.author | Clos, Victòria | - |
dc.contributor.author | Pérez Fernández, Belén | - |
dc.contributor.author | Lavilla Grífols, Rodolfo | - |
dc.contributor.author | Sabaté Lagunas, Raimon | - |
dc.contributor.author | Luque Garriga, F. Xavier | - |
dc.contributor.author | Muñoz-Torrero López-Ibarra, Diego | - |
dc.date.accessioned | 2014-10-29T13:35:43Z | - |
dc.date.available | 2014-10-29T13:35:43Z | - |
dc.date.issued | 2014-09-12 | - |
dc.identifier.issn | 0223-5234 | - |
dc.identifier.uri | http://hdl.handle.net/2445/59194 | - |
dc.description.abstract | Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine<br>6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b<br>d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a<br>d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a<br>d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities. | - |
dc.format.extent | 11 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Elsevier Masson SAS | - |
dc.relation.isformatof | Versió postprint del document publicat a: http://dx.doi.org/10.1016/j.ejmech.2014.07.021 | - |
dc.relation.ispartof | European Journal of Medicinal Chemistry, 2014, vol. 84, p. 107-117 | - |
dc.relation.uri | http://dx.doi.org/10.1016/j.ejmech.2014.07.021 | - |
dc.rights | (c) Elsevier Masson SAS, 2014 | - |
dc.source | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) | - |
dc.subject.classification | Disseny de medicaments | - |
dc.subject.classification | Inhibidors enzimàtics | - |
dc.subject.classification | Malaltia d'Alzheimer | - |
dc.subject.classification | Pèptids | - |
dc.subject.classification | Proteïnes | - |
dc.subject.other | Drug design | - |
dc.subject.other | Enzyme inhibitors | - |
dc.subject.other | Alzheimer's disease | - |
dc.subject.other | Peptides | - |
dc.subject.other | Proteins | - |
dc.title | Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 642499 | - |
dc.date.updated | 2014-10-29T13:35:43Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) Articles publicats en revistes (Institut de Biomedicina (IBUB)) Articles publicats en revistes (Institut de Nanociència i Nanotecnologia (IN2UB)) Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica) |
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File | Description | Size | Format | |
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642499.pdf | 311.22 kB | Adobe PDF | View/Open |
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