Propargylamine-derived multitarget-directed ligands: fighting Alzheimer's disease with monoamine oxidase inhibitors

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a multifaceted pathogenesis. There are at present three Food and Drug Administration-approved drugs based on the one drug, one target paradigm (donepezil, galantamine and rivastigmine) that improve symptoms by inhibiting acetylcholinesterase. However, apart from the beneficial palliative properties, cholinergic drugs have shown little efficacy to prevent the progression of the disease evidencing the unsuitability of this strategy for the complex nature of AD. By contrast, the multifactorial nature of this neurodegenerative disorder supports the most current innovative therapeutic approach based on the one drug, multiple targets paradigm, which suggests the use of compounds with multiple activities at different target sites. Accordingly, the also called multitarget-directed ligand (MTDL) approach has been the subject of increasing attention by many research groups, which have developed a variety of hybrid compounds acting on very diverse targets. The therapeutic potential of monoamine oxidase inhibitors (MAOI) in AD has been suggested due to their demonstrated neuroprotective properties besides their enhancing effect on monoaminergic transmission. Especially, those containing a propargylamine moiety are of particular interest due to their reported beneficial actions. Therefore, targeting MAO enzymes should be considered in therapeutic interventions. This review makes a special emphasis on MTDLs that commonly target MAO enzymes. There is at present an urgent need for real disease-modifying therapies for AD and the MTDL approach makes a breakthrough for the development of new drugs capable of addressing the biological complexity of this disorder.