Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective
monoamine oxidase (
MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable
metal chelator with neuroprotective activity; iii) HLA20A, an
acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and
MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid
peptide, NAPVSIPQ. HLA20A and M30D act as pro-
chelators and can be activated to liberate their respective active
chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these
drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on
antioxidant-chelating potency and AchE and
MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of
amyloid-β and
amyloid-β
protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of
neurotrophic factors, as well as activation of
protein kinase signaling pathways.