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 (IC 50 up to 0.143 µmol L −1 ) and butyrylcholinesterase (IC 50 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 (CH 2 ) 8 spacer, the ability to bind the biometal ions Cu II , Fe II and Zn II was also demonstrated. The obtained characteristics indicated the synthesized conjugates as promising multitarget agents for the treatment of Alzheimer’s disease.