Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

Chalcones have shown a broad spectrum of biological activities with clinical potential against various diseases. The biological activities are mainly attributed to the presence in the chalcones of the α,β-unsaturated carbonyl system, perceived as a potential Michael acceptor. Chalcones could activate the Kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway through a Michael addition reaction with the cysteines of Keap1, which acts as a redox sensor and negative regulator of Nrf2. This modification allows the dissociation of Nrf2 from the cytoplasmic complex with Keap1 and its nuclear translocation. At this level, Nrf2 binds to the antioxidant response element (ARE) and activates the expression of several detoxification, antioxidant and anti-inflammatory genes as well as genes involved in the clearance of damaged proteins. In this regard, the Keap1/Nrf2–ARE pathway is a new potential pharmacological target for the treatment of many chronic diseases. In this review we summarize the current progress in the study of Keap1/Nrf2–ARE pathway activation by natural and synthetic chalcones and their potential pharmacological applications. Among the pharmacological activities highlighted, anti-inflammatory activity was more evident than others, suggesting a multi-target Michael acceptor mechanism for the chalcones involving key regulators of the Nrf2 and nuclear factor- κB (NF-κB) pathways.

Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.

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.