Maria Cecilia Rodrigues Simoes, Flavia Pereira Dias Viegas, Marcella Soares Moreira, Matheus de Freitas Silva, Mariana Maximo Riquiel, Patricia Mattos da Rosa, Maísa Rosa Castelli, Marcelo Henrique dos Santos, Marisi Gomes Soares and Claudio Viegas Pages 2 - 19 ( 18 )
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with a dramatic socioeconomic impact. The progress of AD is characterized by a severe loss in memory and cognition, leading to behavioral changing, depression and death. During the last decades, only a few anticholinergic drugs were launched in the market, mainly acetylcholinesterase inhibitors (AChEIs), with indications for the treatment of initial and moderate stages of AD. The search for new AChEIs, capable to overcome the limitations observed for rivastigmine and tacrine, led Sugimoto and co-workers to the discovery of donepezil. Besides its high potency, donepezil also exhibited high selectivity for AChE and a very low toxicity. In this review, we discuss the main structural and pharmacological attributes that have made donepezil the first choice medicine for AD, and a versatile structural model for the design of novel AChEIs, in spite of multipotent and multitarget-directed ligands. Many recent data from literature transdue great efforts worldwide to produce modifications in the donepezil structure that could result in new bioactive chemical entities with innovative structural pattern. Furthermore, multi-potent ligands have also been designed by molecular hybridization, affording rivastigmine-, tacrine- and huperzine-donepezil potent and selective AChEIs. In a more recent strategy, structural features of donepezil have been used as a model to design multitarget-directed ligands, aiming at the discovery of new effective drug candidates that could exhibit concomitant pharmacological activities as dual or multi- enzymatic inhibitors as genuine innovative therapeutic alternatives for the treatment of AD.
Acetylcholinesterase inhibitors, Alzheimer’s disease, Donepezil, Molecular hybridization, Neurodegenerative disorders, Rational drug design.
Laboratorio de Fitoquimica e Quimica Medicinal – LFQM, Instituto de Quimica, Universidade Federal de Alfenas, 37130-000, Alfenas-MG, Brazil.