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Pyrano[3,2-c]quinoline-6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and beta-Amyloid-Directed Anti-Alzheimer Compounds

AuthorsCamps, Pelayo; Formosa, Xavier; Galdeano, Carles; Muñoz Torrero, Diego; Ramírez, Lorena; Gómez, Elena; Isambert, Nicolás; Lavilla, Rodolfo; Badia, Albert; Clos, M. Victoria; Bartolini, Manuela; Mancini, Francesca; Andrisano, Vincenza; Arce, Mariana P. ; Rodríguez-Franco, María Isabel ; Huertas, Oscar; Dafni, Thomai; Luque Garriga, Francisco Javier
Issue Date2009
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 52 : 5365–5379 (2009)
AbstractTwo isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and selfinduced β-amyloid (Aβ) aggregation, and β-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]- quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Aβ aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.
Publisher version (URL)http://dx.doi.org/10.1021/jm900859q
Appears in Collections:(IQM) Artículos
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