Pyrano[3,2-c]quinoline - 6-chlorotacrine hybrids as a novel family of acetylcholinesterase-and β-amyloid-directed anti-Alzheimer compounds

Pelayo Camps, Xavier Formosa, Carles Galdeano, Diego Muñoz-Torrero, Lorena Ramírez, Elena Gómez, Nicolás Isambert, Rodolfo Lavilla, Albert Badia, M. Victòria Clos, Manuela Bartolini, Francesca Mancini, Vincenza Andrisano, Mariana P. Arce, M. Isabel Rodríguez-Franco, Óscar Huertas, Thomai Dafni, F. Javier Luque

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166 Citations (Scopus)

Abstract

Two 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 self-induced 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. © 2009 American Chemical Society.
Original languageEnglish
Pages (from-to)5365-5379
JournalJournal of Medicinal Chemistry
Volume52
DOIs
Publication statusPublished - 10 Sep 2009

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    Camps, P., Formosa, X., Galdeano, C., Muñoz-Torrero, D., Ramírez, L., Gómez, E., Isambert, N., Lavilla, R., Badia, A., Clos, M. V., Bartolini, M., Mancini, F., Andrisano, V., Arce, M. P., Rodríguez-Franco, M. I., Huertas, Ó., Dafni, T., & Luque, F. J. (2009). Pyrano[3,2-c]quinoline - 6-chlorotacrine hybrids as a novel family of acetylcholinesterase-and β-amyloid-directed anti-Alzheimer compounds. Journal of Medicinal Chemistry, 52, 5365-5379. https://doi.org/10.1021/jm900859q