title: Synthesis of new N-benzylpiperidine derivatives as cholinesterase inhibitors with β-amyloid anti-aggregation properties and beneficial effects on memory in vivo.
abstract: 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 β-amyloid are the predominant biological targets in the search for new anti-Alzheimer's agents. Our aim was to combine both anticholinesterase and β-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 β-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 μM) that has β-amyloid anti-aggregation activity (72.5% inhibition at 10 μM) 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.
authors: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Medical College, Jagiellonian University, Kraków, Poland.
authors: Anna
authors: A
authors: Więckowska
authors: Department of Organic Chemistry, Medical College, Jagiellonian University, Kraków, Poland.
authors: Krzysztof
authors: K
authors: Więckowski
authors: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Medical College, Jagiellonian University, Kraków, Poland.
authors: Marek
authors: M
authors: Bajda
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors: Boris
authors: B
authors: Brus
authors: Department of Pharmacodynamics, Medical College, Jagiellonian University, Kraków, Poland.
authors: Kinga
authors: K
authors: Sałat
authors: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Medical College, Jagiellonian University, Kraków, Poland.
authors: Paulina
authors: P
authors: Czerwińska
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
authors: Stanislav
authors: S
authors: Gobec
authors: Department of Pharmacodynamics, Medical College, Jagiellonian University, Kraków, Poland.
authors: Barbara
authors: B
authors: Filipek
authors: Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Medical College, Jagiellonian University, Kraków, Poland. Electronic address: mfmalaws@cyf-kr.edu.pl.
authors: Barbara
authors: B
authors: Malawska
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002091:Butyrylcholinesterase / Q000737:chemistry*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D000077265:Donepezil; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D010797:Phthalimides / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D066329:Protein Aggregates / Q000187:drug effects; D012601:Scopolamine; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D007211:Indoles; D018696:Neuroprotective Agents; D010797:Phthalimides; D010880:Piperidines; D066329:Protein Aggregates; D000077265:Donepezil; D012601:Scopolamine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer’s disease; Blood–brain barrier permeability; Cholinesterase inhibitors; Indole; N-benzylpiperidine; Passive avoidance; Phthalimide; β-Amyloid aggregation