Donepezil-Based Central Acetylcholinesterase Inhibitors by Means of a “Bio-Oxidizable” Prodrug Strategy: Design, Synthesis, and in Vitro Biological Evaluation

With
the aim of reducing side effects of acetylcholinesterase inhibitors
(AChEIs) during symptomatic treatment of Alzheimer’s disease,
we report herein a new class of donepezil-based “bio-oxidizable”
prodrugs 1 designed to be converted into dual binding site AChEIs
2. While most of indanone-derived N-benzylpyridinium
salts 2 revealed to be highly potent dual binding site hAChEIs (IC50 up to 3 nM), outperforming the standard drug donepezil (IC50 = 11 nM), most of the corresponding 1,4-dihydropyridines
1 were found to be inactive. Promisingly, whereas the selected prodrug 1r showed good permeability in the PAMPA-BBB model and high
in vitro antioxidant activity, its conversion to AChEI 2r could be
easily achieved under mild conditions when incubated in various oxidizing
media. Lastly, both compounds 1r and 2r did
not show genotoxicity in vitro and displayed high LD50 values
in mice, making this prodrug 1r/drug 2r couple
a good candidate for further in vivo biological experiments.