Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo

Due to the complex nature of Alzheimer's disease, multi-target-directed ligand approaches are one of the most promising strategies in the search for effective treatments. Acetylcholinesterase, butyrylcholinesterase and beta-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and beta-amyloid anti-aggregation activities in one molecule, and to determine the therapeutic potential in vivo. We designed and synthesized 28 new compounds as derivatives of donepezil that contain the N-benzylpiperidine moiety combined with the phthalimide or indole moieties. Most of these test compounds showed micromolar activities against cholinesterases and aggregation of b-amyloid, combined with positive results in blood-brain barrier permeability assays. The most promising compound 23 (2-(8-(1-(3-chlorobenzyl)piperidin-4-ylamino) octyl) isoindoline-1,3-dione) is an inhibitor of butyrylcholinesterase (IC50 = 0.72 mu M) that has beta-amyloid anti-aggregation activity (72.5% inhibition at 10 mu M) and can cross the blood-brain barrier. Moreover, in an animal model of memory impairment induced by scopolamine, the activity of 23 was comparable to that of donepezil. The selected compound 23 is an excellent lead structure in the further search for new anti-Alzheimer's agents. (C) 2015 Elsevier Ltd. All rights reserved.