title: Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds.
abstract: Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.
authors: Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.
authors: Pelayo
authors: P
authors: Camps
authors: Xavier
authors: X
authors: Formosa
authors: Carles
authors: C
authors: Galdeano
authors: Diego
authors: D
authors: Muñoz-Torrero
authors: Lorena
authors: L
authors: Ramírez
authors: Elena
authors: E
authors: Gómez
authors: Nicolás
authors: N
authors: Isambert
authors: Rodolfo
authors: R
authors: Lavilla
authors: Albert
authors: A
authors: Badia
authors: M Victòria
authors: MV
authors: Clos
authors: Manuela
authors: M
authors: Bartolini
authors: Francesca
authors: F
authors: Mancini
authors: Vincenza
authors: V
authors: Andrisano
authors: Mariana P
authors: MP
authors: Arce
authors: M Isabel
authors: MI
authors: Rodríguez-Franco
authors: Oscar
authors: O
authors: Huertas
authors: Thomai
authors: T
authors: Dafni
authors: F Javier
authors: FJ
authors: Luque
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002417:Cattle; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D007536:Isomerism; D008567:Membranes, Artificial; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010539:Permeability; D011485:Protein Binding / Q000187:drug effects; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C098212:6-chlorotacrine; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D008567:Membranes, Artificial; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D053829:Amyloid Precursor Protein Secretases