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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.

In the last years, Medicinal Chemistry is tracking down for novel tools and alternatives capable to bring to light better agility, safety and a more efficient address in the design and prospection of drug candidates. In this context, strategies for drug discovery focusing the development of ligands that act on specific target have been discussed, considering that they have limited application on multifactorial diseases, where a set of biochemical events and protein targets are involved. During the last decade, a novel polypharmacology based approach has emerged for planning ligands, aiming the discovery of chemical entities capable to act simultaneously on multiple molecular targets. Since 2005, the literature has reported many studies that use this innovative strategy for drug design against Alzhei e s disease (AD). AD is a neurodegenerative illness, characterized by a set of interconnected events involving intra and extracellular protein fragment deposits, the onset of a complex neuroinflammatory process, mitochondrial dysfunction, apoptosis and neuronal death. As a consequence of the disease progress, the patient is affected by memory and cholinergic deficits, motor and functional impairment, and death. In this brief review, our goal was to report the most recent advances (2013-2014) on medicinal chemistry for the design and discovery of novel multi-target drug candidate prototypes potentially useful for AD treatment. This work is complementary to another review recently published by our group covering the early 2005-2012 period. In most of the works discussed herein, the commercial drugs rivastigmine, tacrina, donepezil and galanthamine have been used as models of acetilcolinesterase inhibitors for the design of novel molecular hybrids with multiple action profile. In other cases, natural products such as curcumine, resveratrol, berberine and quercetin have been elected due to their neuroprotective, antiapoptotic, anti-inflammatory and antioxidant characteristics for planning new chemical entities with innovative properties and therapeutic potential for a more effective AD treatment.

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