Conjugates of tacrine with aminomethylidene derivatives of ethyl acetoacetate as promising agents for the treatment of Alzheimer's disease.

A series of new conjugates of tacrine with ethyl 2-aminomethylidene-3-oxobutanoate with a spacer length of 4, 6, and 8 methylene groups was synthesized. The synthesized conjugates were shown to be effective inhibitors of acetylcholinesterase (IC50 up to 0.143 µmol L−1) and butyrylcholinesterase (IC50 up to 0.024 µmol L−1), with the inhibitory activity increasing with the spacer elongation. The new conjugates, as their diethyl malonate analogs, demonstrated a potential ability to block the AChE-induced β-amyloid aggregation and inhibited the self-aggregation of β-amyloid (1–42) with maximum activity at the level of the standard compound myricetin for derivatives with the octamethylene spacer. For the lead compound, a conjugate of tacrine with ethyl 2-aminomethylidene-3-oxobutanoate with the (CH2)8 spacer, the ability to bind the biometal ions CuII, FeII and ZnII was also demonstrated. The obtained characteristics indicated the synthesized conjugates as promising multitarget agents for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]