Discovery of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal as multifunctional agents for the treatment of Alzheimer's disease.

Due to the multifactorial nature of Alzheimer's disease (AD), effective multi-targeted directed ligands (MTDLs) are urgently needed for its treatment as single-target drugs currently encounter therapeutic challenges. Two series of new 4-aminoquinoline derivatives containing an amine or hydroxamic acid terminal were designed, synthesized and evaluated for their cholinesterase inhibition, antioxidant and metal-ion chelation properties. Among them, hydroxamic acid-containing compounds 7r and 7f exhibited the best inhibitor activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), respectively, with the corresponding IC values of 0.41 and 1.06 μM, which were superior to those of rivastigmine (IC = 5.26, 2.02 μM, respectively). Moreover, compounds 7r and 7f presented excellent ABTS radical scavenging efficiency and selective metal-ion chelation ability such as Cu and Fe. Both molecular docking and enzyme kinetic analysis revealed that compound 7r was a mixed-type inhibitor of AChE. Additionally, the ADME prediction indicated that compounds 7r and 7f have suitable pharmacokinetic and drug-like properties. Furthermore, they demonstrated good safety and blood-brain barrier permeability in cytotoxicity assays and in vivo experiments, respectively. These findings strongly suggest that the 4-aminoquinoline derivatives containing a hydroxamic acid terminal have great potential as promising MTDLs for the treatment of AD, opening new avenues for future therapeutic strategies.