Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds

TitlePyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds
Publication TypeJournal Article
Year of Publication2009
AuthorsCamps, P, Formosa X, Galdeano C, Munoz-Torrero D, Ramirez L, Gomez E, Isambert N, Lavilla R, Badia A, Clos MV, Bartolini M, Mancini F, Andrisano V, Arce MP, Rodriguez-Franco MI, Huertas O, Dafni T, Luque FJ
JournalJournal of medicinal chemistry
Pagination5365 - 5379
Date Published2009/09/10/
KeywordsAcetylcholinesterase/metabolism; Alzheimer Disease/drug therapy; Amyloid Precursor Protein Secretases/antagonists & inhibitors; Amyloid beta-Protein/metabolism; Animals; Binding Sites; Blood-Brain Barrier/drug effects/metabolism; Butyrylcholinesterase/met, Artificial; Mice; Models, Molecular; Molecular Conformation; Permeability; Protein Binding/drug effects; Tacrine/analogs & derivatives/chemistry/metabolism/pharmacology/therapeutic use
AbstractTwo 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.