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Bioorg Med Chem. 2015 Apr 1;23(7):1629-37. doi: 10.1016/j.bmc.2015.01.045. Epub 2015 Feb 9.

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

Author information

1
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
2
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
3
Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland. Electronic address: mfmalaws@cyf-kr.edu.pl.

Abstract

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 (hAChE IC50=0.361μM). 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.

KEYWORDS:

Alzheimer’s disease; Cholinesterase inhibitors; Multi-target-directed ligands; PAMPA-BBB assay; β-Amyloid aggregation

PMID:
25707322
DOI:
10.1016/j.bmc.2015.01.045
[Indexed for MEDLINE]

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