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.