Conjugates of Tacrine with Salicylamide as Promising Multitarget Agents for Alzheimer's Disease

New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC50 to 0.224 μM) and butyrylcholinesterase (BChE, IC50 to 0.0104 μM) inhibitory activities. They were also rather poor inhibitors of carboxylesterase, suggesting a low tendency to exert potential unwanted drug‐drug interactions in clinical use. The conjugates were mixed‐type reversible inhibitors of both cholinesterases and demonstrated dual binding to the catalytic and peripheral anionic sites of AChE in molecular docking that, along with experimental results on propidium iodide displacement, suggest their potential to block AChE‐induced β‐amyloid aggregation. The new conjugates exhibited high ABTS.+‐scavenging activity. N‐(6‐(1,2,3,4‐Tetrahydroacridin‐9‐ylamino)hexyl)salicylamide is a lead compound that also demonstrates metal chelating ability toward Cu2+, Fe2+ and Zn2+. Thus, the new conjugates have displayed the potential to be multifunctional anti‐AD agents for further development. Conjugates of tacrine and salicylamide were synthesized as potential multifunctional anti‐AD agents. The compounds have high anticholinesterase (IC50 AChE to 0.22 μM, IC50 BChE to 0.01 μM) and low anti‐CES activity, displaced propidium iodide from the AChE PAS, being in agreement with the results of molecular docking. The conjugates exhibited ABTS+‐scavenging (TEAC to 0.9) and metal‐chelating activity.