Recent Applications of the Multi-Target Directed Ligands Approach for the Treatment of Alzheimer's Disease

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 Alzheimer'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, mitochondria! 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.