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Closed Access item Tacrine – Melatonin Hybrids as Multifunctional Agents for Alzheimer’s Disease, with Cholinergic, Antioxidant, and Neuroprotective Properties

Authors:Fernández Bachiller, María Isabel
Pérez, Concepción
Campillo, Nuria Eugenia
Páez, Antonio
González Muñoz, Gema Cristina
Usán, Paola
García Palomero, Esther
López, Manuela G.
Villarroya, Mercedes
García, Antonio G.
Martínez, Ana
Rodríguez Franco, María Isabel
Keywords:Alzheimer's disease, cholinergic, drug design, molecular modeling, neuroprotection
Issue Date:2009
Publisher:John Wiley & Sons
Citation:ChemMedChem 4 (5) : 828–841 (2009)
Abstract:Tacrine–melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer’s disease. These compounds may simultaneously palliate intellectual deficits and protect the brain against both b-amyloid (Ab) peptide and oxidative stress. They show improved cholinergic and antioxidant properties, and are more potent and selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub-micromolar concentrations they efficiently displace the binding of propidium iodide from the PAS and could thus inhibit Ab peptide aggregation promoted by AChE. Moreover, they also inhibit Ab self-aggregation and display neuroprotective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as Ab25–35, H2O2, and rotenone. Finally, they exhibit low toxicity and may be able to penetrate the central nervous system according to an in vitro parallel artificial membrane permeability assay for the blood–brain barrier (PAMPA-BBB).
Publisher version (URL):http://dx.doi.org/10.1002/cmdc.200800414
URI:http://hdl.handle.net/10261/36454
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Appears in Collections:(IQM) Artículos

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