Hybrid-Based Multi-Target Ligands for the Treatment of Alzheimer's Disease

Angela      Rampa; Federica      Belluti; Silvia      Gobbi; Alessandra      Bisi

Abstract

Progresses in medicinal chemistry over the last few years have focused on the design and synthesis of hybrid compounds, molecules encompassing in a single scaffold two pharmacophores from known entities endowed with well established biological activities. The interest in this topic is related to the increasing emphasis on the identification of the different factors involved in a number of disorders, such as the complex multifactorial Alzheimers disease (AD), and hybrid- based strategy has become a focal point in this medicinal chemistry field since it could lead to derivatives with an improved biological profile. Using this strategy, acetylcholinesterase inhibitors (AChEIs) have been extensively coupled with properly selected bioactive molecules to obtain homo- and heterodimers endowed with increased potency together with supplementary actions. In the past decade the inhibition of the AChE induced aggregation of the β-amyloid peptide into the senile plaques, which is a key event in the neurotoxic cascade of AD, has been considered a relevant approach leading to several dual binding site inhibitors, able to contact both the peripheral anionic site of AChE and the active site. In recent years, pioneering efforts have been performed to obtain novel AChEIs that, beyond the capability to inhibit AChE, were able to hit a number of specific AD targets. In particular, these compounds proved to possess antioxidant, anti-inflammatory, or neuroprotective activities, useful to block or revert the progression of the disease. This review summarizes the progresses that have been made in the design of hybrid molecules for the treatment of AD.

Keywords: Acetylcholinesterase inhibitors, Alzheimer's disease, amyloid beta peptide, drug design, hybrid compounds, multitarget, antioxidant, anti-inflammatory, neurotoxic cascade, neuropathologic hallmarks, neurotransmitter systems, cholinergicsynapses, neurotransmitter ACh, amyloid hypothesis, proteolytic cleavages, gastrointestinal disorders