Utilizad este identificador para citar o enlazar este documento: http://hdl.handle.net/2072/232917

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
Di Pietro, O.; Viayna, E.; 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
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.
13-06-2014
Acetilcolinesterasa
Farmacologia experimental
Inhibidors enzimàtics
Malaltia d'Alzheimer
Síntesi orgànica
Acetylcholinesterase
Experimental pharmacology
Enzyme inhibitors
Alzheimer's disease
Organic synthesis
(c) Elsevier Masson SAS, 2014
Artículo
info:eu-repo/semantics/acceptedVersion
Elsevier Masson SAS
         

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Di Pietro, O.; Viayna, E.; 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
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