First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC50 = 0.4 µM) and (h)MAO-B (IC50 = 6.4 µM).

Amyloid Cascade Hypothesis for the Treatment of Alzheimer’s Disease: Progress and Challenges

“…Monoamine oxidase (MAO) could also influence the cleavage of APP by adjusting the γ-secretase [ 55 ]. There have been several marketed monoamine oxidase inhibitors (MAOI) such as Rasagiline (8) and Ladostigil (9) used for the treatment of Parkinson's disease (PD), AD, and depression, which showed a degree of neuroprotective effects [ 56 , 57 ]. Amongst them, ladostigil was designed from the pharmacophores of rasagiline and rivastigmine (10), an inhibitor of both acetyl-cholinesterase (Ache) and butyrylcholinesterase (Bche) and showed multi-target action.…”

Discovery and In Vivo Proof of Concept of a Highly Potent Dual Inhibitor of Soluble Epoxide Hydrolase and Acetylcholinesterase for the Treatment of Alzheimer’s Disease

“…Alzheimer’s disease (AD), the most prevalent neurodegenerative disease, is one of such multifactorial diseases that lack an effective treatment, which would greatly benefit from the development of multitarget drugs. − A key step of multitarget drug design is the selection of the targets, whose modulation should result in additive or synergistic effects, preferably on key pathogenic mechanisms …”

Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer’s Disease

“…Actually, treatment strategies against AD are limited and many clinical trials have been conducted to clear misfolded β-amyloid proteins from brain tissues, but without additional outcomes. For instance, acetylcholinesterase (AChE) inhibitors, including donepezil or noncompetitive NMDA receptor antagonists, are approved to treat this pathology [ 13 ]. However, these drugs were not able to slow down disease progression and caused adverse effects, such as diarrhea, nausea or insomnia [ 14 ].…”