DOI: 10.1002/cmdc.200800414 Tacrine–Melatonin Hybrids as Multifunctional Agents for Alzheimer’s Disease, with Cholinergic, Antioxidant, and Neuroprotective Properties María Isabel Fernµndez-Bachiller, [a] Concepción PØrez, [a] Nuria Eugenia Campillo, [a] Juan Antonio Pµez, [a] Gema Cristina Gonzµlez-MuÇoz, [a] Paola Usµn, [b] Esther García-Palomero, [b] Manuela G. López, [c] Mercedes Villarroya, [c] Antonio G. García, [c, d] Ana Martínez, [b, e] and María Isabel Rodríguez-Franco* [a] Introduction Alzheimer’s disease (AD), the most common cause of dementia in elderly people, is a complex neurodegenerative illness of the central nervous system (CNS), characterized by progressive memory loss and other cognitive impairments. The etiology of AD is not completely known, although there are diverse hall- marks such as b-amyloid (Ab) deposits, t-protein aggregation, oxidative damage in cell structures, and low levels of acetyl- choline (ACh) that seem to play significant roles in the dis- ease. [1] Several pharmacological strategies have emerged over the last decades including cholinergic [2] and noncholinergic inter- ventions. [3] The cholinergic approach launched four drugs on the market for management of the disease: the acetylcholines- terase inhibitors (AChE-Is) tacrine, donepezil, rivastigmine, and galantamine, which increase neurotransmission at cholinergic synapses in the brain, improving cognition. [4] The only ap- proved noncholinergic drug for AD is memantine, an N- methyl-d-aspartate (NMDA) receptor antagonist, which im- proves cognition and mental functions by restoration of ho- meostasis in the glutamatergic system. [5] Nowadays many can- didates with other pharmacological profiles are in phase III clinical trials, such as the g-secretase inhibitor LY450139, the presenilin modulator docosahexaenoic acid, the PPAR-g agonist rosiglitazone, and the anticholesterol agent simvastatin, among others. [6] To date, the approved AChE-Is have been considered as simple symptomatic short-term drugs that improve memory but do not stop neurodegeneration. However, clinical data emerging from long-term trials suggests that the rate of neu- rodegenerative progression of AD is decreased in patients treated with these drugs, and that a disease-modifying effect may take place. [7] Moreover, the recent development of neuroi- maging techniques has provided empirical evidence of these beneficial effects, showing that patients treated with AChE-Is do not show the widespread cortical atrophic changes associ- ated with AD. [8] The disease-modifying effects observed with the use of AChE-Is might be related to their primary mode of action or [a] Dr. M. I. Fernµndez-Bachiller, Dr. C. PØrez, Dr. N. E. Campillo, Dr. J. A. Pµez, G. C. Gonzµlez-MuÇoz, Dr. M. I. Rodríguez-Franco Instituto de Química MØdica Consejo Superior de Investigaciones Científicas (CSIC) C/Juan de la Cierva 3, 28006 Madrid (Spain) Fax: (+ 34) 915 644 853 E-mail : IsabelRguez@iqm.csic.es [b] P. Usµn, Dr. E. García-Palomero, Dr. A. Martínez Noscira S.A., Avda. de la Industria 52, 28760 Madrid (Spain) [c] Dr. M. G. López, Dr. M. Villarroya, Dr. A. G. García Instituto Teófilo Hernando, Facultad de Medicina Universidad Autónoma de Madrid (UAM) C/Arzobispo Morcillo 4, 28029 Madrid (Spain) [d] Dr. A. G. García Servicio de Farmacología Clínica Hospital Universitario de la Princesa C/Diego de León 62, 28006 Madrid (Spain) [e] Dr. A. Martínez current address: Instituto de Química MØdica (CSIC) C/Juan de la Cierva 3, 28006 Madrid (Spain) Tacrine–melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer’s disease. These compounds may simultaneously palliate intellectual defi- cits and protect the brain against both b-amyloid (Ab) peptide and oxidative stress. They show improved cholinergic and anti- oxidant properties, and are more potent and selective inhibi- tors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the cat- alytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub-micromolar concentrations they efficiently dis- place the binding of propidium iodide from the PAS and could thus inhibit Ab peptide aggregation promoted by AChE. More- over, they also inhibit Ab self-aggregation and display neuro- protective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as Ab 25–35 , H 2 O 2 , 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). 828  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2009, 4, 828 – 841 MED