Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease.

New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC: AChE, 0.265-4.24 μM; BChE, 0.01-0.64 μM) but poor activity against off-target carboxylesterase (CES). Specifically, conjugates with a (CH) spacer showed the highest AChE and BChE inhibition: 3-16 times more effective than amiridine. Salicylamides 7b and 7c had the maximum BChE/AChE selectivity ratios: 193 and 138, respectively. Conjugates were mixed-type reversible inhibitors of both cholinesterases and displaced propidium from the AChE peripheral anionic site (PAS) at the level of donepezil. All conjugates inhibited Aβ self-aggregation in the thioflavin test; inhibition increased with spacer elongation, being greatest for (CH). The results agreed with molecular docking to AChE, BChE, and Aβ. Conjugates exhibited high 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)-scavenging activity comparable to the standard antioxidant Trolox, and they showed the ability to bind Cu, Fe, and Zn. Conjugates had favorable predicted intestinal absorption and blood-brain barrier permeability. Altogether, the results indicate that the new conjugates possess potential for further development as multifunctional anti-AD drug candidates.