Acetylcholinesterase Inhibition of Diversely Functionalized Quinolinones for Alzheimer's Disease Therapy.

In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones ( QN1 - 19 ) and 13 dihydroquinolinones ( DQN1 - 13 ) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8 , QN9 , and DQN7 displayed promising human recombinant acetylcholinesterase ( hr AChE) and butyrylcholinesterase ( hr BuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hr AChE (IC ₅₀ = 0.29 µM), with K _i value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.