Novel 8-Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer's Disease

We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and beta-amyloid (A beta)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit A beta self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1b), 7-((4-(2-methoxybenzyl) piperazin-1-yl) methyl)-8-hydroxyquinoline (2b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity in vitro. Importantly, in the case of 2b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.