Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/59194
Title: Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies
Author: Di Pietro, O.
Pérez-Areales, F. Javier
Juárez-Jiménez, Jordi
Espargaró Colomé, Alba
Clos Guillén, M. Victòria
Pérez Fernández, Belén
Lavilla Grífols, Rodolfo
Sabaté Lagunas, Raimon
Luque Garriga, F. Xavier
Muñoz-Torrero López-Ibarra, Diego
Keywords: Disseny de medicaments
Inhibidors enzimàtics
Malaltia d'Alzheimer
Pèptids
Proteïnes
Drug design
Enzyme inhibitors
Alzheimer's disease
Peptides
Proteins
Issue Date: 12-Sep-2014
Publisher: Elsevier Masson SAS
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.
Note: Versió postprint del document publicat a: http://dx.doi.org/10.1016/j.ejmech.2014.07.021
It is part of: European Journal of Medicinal Chemistry, 2014, vol. 84, p. 107-117
Related resource: http://dx.doi.org/10.1016/j.ejmech.2014.07.021
URI: http://hdl.handle.net/2445/59194
ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
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))

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