Novel Tacrine – 8-Hydroxyquinoline Hybrids as Multifunctional Agents for the Treatment of Alzheimer’s Disease, with Neuroprotective, Cholinergic, Antioxidant, and Copper-Complexing Properties

Tacrine and PBT2 (an 8-hydroxyquinoline derivative) are well-known drugs that inhibit cholinesterases and decrease β-amyloid (Aβ) levels by complexation of redox-active metals, respectively. In this work, novel tacrine-8-hydroxyquinoline hybrids have been designed, synthesized, and evaluated as potential multifunctional drugs for the treatment of Alzheimer’s disease. At nano- and subnanomolar concentrations they inhibit human acetyl- and butyrylcholinesterase (AChE and BuChE), being more potent than tacrine. They also displace propidium iodide from the peripheral anionic site of AChE and thus could be able to inhibit Aβ aggregation promoted by AChE. They show better antioxidant properties than Trolox, the aromatic portion of vitamin E responsible for radical capture, and display neuroprotective properties against mitochondrial free radicals. In addition, they selectively complex Cu(II), show low cell toxicity, and could be able to penetrate the CNS, according to an in vitro blood-brain barrier modelThe authors gratefully acknowledge the financial support of SpanishMinistry of Science and Innovation (Projects SAF2006-01249, SAF2009-13015-C02-01, and SAF2009-12150), Community ofMadrid (Programa de Actividades de IþDentre Grupos de Investigación en Biociencias, Project S-SAL/0275/2006), and the Institute ofHealth Carlos III (Projects Red RENEVAS, RETICS-RD06/0026). The fellowships toM.I.F.-B. and G.C.G.-M. from CSIC are also acknowledged.Peer reviewe