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 beta-amyloid (A-beta) aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position than 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 which 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 A-beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.
E. Viayna, P. Camps, X. Formosa, C. Galdeano, T. Gómez, D. Muñoz-Torrero, et al. (2009). NOVEL DONEPEZIL-BASED INHIBITORS OF CHOLINESTERASES AND ACETYLCHOLINESTERASE-INDUCED BETA-AMYLOID AGGREGATION.
NOVEL DONEPEZIL-BASED INHIBITORS OF CHOLINESTERASES AND ACETYLCHOLINESTERASE-INDUCED BETA-AMYLOID AGGREGATION
BARTOLINI, MANUELA;MANCINI, FRANCESCA;ANDRISANO, VINCENZA;
2009
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 beta-amyloid (A-beta) aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position than 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 which 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 A-beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
