Isoindoline-1,3-dione derivatives targeting cholinesterases: Design, synthesis and biological evaluation of potential anti-Alzheimer’s agents.

Alzheimer’s disease is a fatal neurodegenerative disorder with a complex etiology. Because the available therapy brings limited benefits, the effective treatment for Alzheimer’s disease remains the unmet challenge. Our aim was to develop a new series of donepezil-based compounds endowed with inhibitory properties against cholinesterases and β-amyloid aggregation. We designed the target compounds as dual binding site acetylcholinesterase inhibitors with N -benzylamine moiety interacting with the catalytic site of the enzyme and an isoindoline-1,3-dione fragment interacting with the peripheral anionic site of the enzyme. The results of pharmacological evaluation lead us to identify a compound 3b as the most potent and selective human acetylcholinesterase inhibitor ( h AChE IC 50 = 0.361 μM). Kinetic studies revealed that 3b inhibited acetylcholinesterase in non-competitive mode. The result of the parallel artificial membrane permeability assay for the blood–brain barrier indicated that the compound 3b would be able to cross the blood–brain barrier and reach its biological targets in the central nervous system. The selected compound 3b represents a potential lead structure for further development of anti-Alzheimer’s agents. [ABSTRACT FROM AUTHOR]