From Anti-Parkinson’s Drug Rasagiline to Novel Multitarget Iron Chelators with Acetylcholinesterase and Monoamine Oxidase Inhibitory and Neuroprotective Properties for Alzheimer’s Disease

Abstract

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 multimodal compounds, as follows: the brain selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity, M30; the chelating with neuroprotective activity, HLA20; the acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity, HLA20A; the AChE-MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity, M30D; and neuroprotective peptide NAPVSIPQ analogs. Among them, 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, 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 the major role of oxidative stress (OS) due to accumulation of iron in AD brains and formation of free oxygen radicals, modulation of amyloid-β (Aβ) and amyloid precursor protein expression/processing and tau, induction of cell cycle arrest; inhibition of neuronal death markers, upregulation of neurotrophic factors, as well as activation of protein kinase C and mitogenactivated protein kinase signaling pathways.