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Multiple Ligands Targeting Cholinesterases and β‐Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore
Author(s) -
Szałaj Natalia,
Bajda Marek,
Dudek Katarzyna,
Brus Boris,
Gobec Stanislav,
Malawska Barbara
Publication year - 2015
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201500117
Subject(s) - pharmacophore , chemistry , acetylcholinesterase , moiety , isoindoline , huperzine a , butyrylcholinesterase , acetylcholinesterase inhibitor , amyloid precursor protein , benzylamine , donepezil , stereochemistry , chemical synthesis , pharmacology , enzyme , combinatorial chemistry , biochemistry , in vitro , alzheimer's disease , aché , dementia , organic chemistry , biology , medicine , disease , pathology
Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti‐AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N ‐benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin‐1‐one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC 50 = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non‐competitive acetylcholinesterase inhibitor and is able to cross the blood–brain barrier in vitro . We believe that compound 8b represents an important lead compound for further development as potential anti‐AD agent.