title: Tacrine-flurbiprofen hybrids as multifunctional drug candidates for the treatment of Alzheimer's disease.
abstract: Five tacrine-flurbiprofen hybrid compounds (3a-e) were synthesized as multi-target-directed compounds for the treatment of Alzheimer's disease. Compared to tacrine, two compounds (3d and 3e) showed better acetylcholinesterase (AChE) inhibitory activity and others (3b-e) better or the same butyrylcholinesterase (BuChE) inhibitory activity. Notably, 3d showed a mixed-type inhibitory action for AChE, indicating a "dual-binding site action" of both toward the catalytic active site (CAS) and the peripheral anionic site (PAS), whereas for BuChE, a competitive inhibitory action was observed. Furthermore, a cell-based assay on amyloid-β inhibition demonstrated that the selected target compound 3d effectively inhibits the formation of amyloid-β in vitro.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, P. R. China; Center of Drug Discovery, China Pharmaceutical University, Nanjing, P. R. China; Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Jena, Germany.
authors.forename: Yao
authors.initials: Y
authors.lastname: Chen
authors.forename: Jianfei
authors.initials: J
authors.lastname: Sun
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D013619:Tacrine; D005480:Flurbiprofen; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Alzheimer's disease; Amyloid-β; Cholinesterase inhibitor; Flurbiprofen; Tacrine