Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/54915
Title: 1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies
Author: Di Pietro, O.
Viayna, Elisabet
Vicente García, Esther
Bartolini, Manuela
Ramón, Rosario
Juárez-Jiménez, Jordi
Clos Guillén, M. Victòria
Pérez Fernández, Belén
Andrisano, Vincenza
Luque Garriga, F. Xavier
Lavilla Grífols, Rodolfo
Muñoz-Torrero López-Ibarra, Diego
Keywords: Acetilcolinesterasa
Disseny de medicaments
Inhibidors enzimàtics
Malaltia d'Alzheimer
Compostos heterocíclics
Acetylcholinesterase
Drug design
Enzyme inhibitors
Alzheimer's disease
Heterocyclic compounds
Issue Date: 12-Feb-2014
Publisher: Elsevier Masson SAS
Abstract: A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.
Note: Versió postprint del document publicat a: http://dx.doi.org/10.1016/j.ejmech.2013.12.008
It is part of: European Journal of Medicinal Chemistry, 2014, vol. 73, p. 141-152
Related resource: http://dx.doi.org/10.1016/j.ejmech.2013.12.008
URI: http://hdl.handle.net/2445/54915
ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)
Articles publicats en revistes (Institut de Biomedicina (IBUB))
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

Files in This Item:
File Description SizeFormat 
630673.pdf674.5 kBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.