Novel donepezil-based inhibitors of acetyl- and butyrylcholinesterase and acetylcholinesterase-induced β-amyloid aggregation

Pelayo Camps, Xavier Formosa, Carles Galdeano, Tània Gómez, Diego Muñoz-Torrero, Michele Scarpellini, Elisabet Viayna, Albert Badia, M. Victòria Clos, Antoni Camins, Mercè Pallàs, Manuela Bartolini, Francesca Mancini, Vincenza Andrisano, Joan Estelrich, Mònica Lizondo, Axel Bidon-Chanal, F. Javier Luque

Research output: Contribution to journalArticleResearchpeer-review

159 Citations (Scopus)

Abstract

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced Aβ aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant Aβ antiaggregating activity, which makes them promising anti-Alzheimer drug candidates. © 2008 American Chemical Society.
Original languageEnglish
Pages (from-to)3588-3598
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
Publication statusPublished - 26 Jun 2008

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