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 (A-beta) aggregation and gamma-secretase (BACE-1). 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. Molecular modeling studies have confirmed the dual site binding of these hybrids, which retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in vitro A-beta anti-aggregating effect and BACE-1 inhibitory activity, thus constituting promising anti-Alzheimer drug candidates.
C. Galdeano, P. Camps, X. Formosa, D. Muñoz-Torrero, L. Ramírez, E. Gómez, et al. (2009). SYNTHESIS, PHARMACOLOGICAL EVALUATION, AND MOLECULAR MODELING OF A NOVEL FAMILY OF 6-CHLOROTACRINE-BASED DUAL BINDING SITE ACETYLCHOLINESTERASE INHIBITORS.
SYNTHESIS, PHARMACOLOGICAL EVALUATION, AND MOLECULAR MODELING OF A NOVEL FAMILY OF 6-CHLOROTACRINE-BASED DUAL BINDING SITE ACETYLCHOLINESTERASE INHIBITORS
BARTOLINI, MANUELA;MANCINI, FRANCESCA;ANDRISANO, VINCENZA;
2009
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 (A-beta) aggregation and gamma-secretase (BACE-1). 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. Molecular modeling studies have confirmed the dual site binding of these hybrids, which retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine, while exhibiting a significant in vitro A-beta anti-aggregating effect and BACE-1 inhibitory activity, thus constituting promising anti-Alzheimer drug candidates.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
