Wang_2025_Molecules_30_

A novel series of multifunctional tacrine-quinoline hybrids were designed, synthesized, and evaluated as potential anti-Alzheimer's agents. These compounds incorporate tacrine for cholinesterase's inhibition and 8-hydroxyquinoline for metal chelation. Piperazine was selected as a linker to provide conformational flexibility and to create favorable cation-Pi interactions with residues in the mid-gorge region of AChE, enhancing dual-site binding with AChE to inhibit Abeta aggregation. In vitro studies demonstrated submicromolar inhibitory activity toward both AChE and BuChE, particularly for compounds 16e (IC(50) = 0.10 microM for AChE, 0.043 microM for BuChE) and 16h (IC(50) = 0.21 microM for AChE, 0.10 microM for BuChE). These compounds also exhibited potent inhibition of self-induced Abeta(1-42) aggregation (16e: 80.5% +/- 4.4%, 16h: 93.2% +/- 3.9% at 20 microM). Kinetic analyses revealed mixed-type inhibition, suggesting dual binding to both CAS and PAS of AChE. UV-vis spectrometry confirmed the chelation of Cu(2+) and Zn(2+) ions by the 8-hydroxyquinoline moiety. These findings highlight the tacrine-quinoline scaffold as a promising platform for the discovery of a multitarget-directed anti-AD drug.