Pyrano[3,2-c]quinoline−6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-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.

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…Such linkages have proven to be chemically stable at physiological pH up to 4 days at 37 ºC in a structurally related family of hybrid compounds. 41 Chains from 5 to 11 methylene groups were considered for the linkers (in hybrids 7a-g, Scheme 1), to afford suitable distances between huprine and rhein moieties to achieve a dual site binding to AChE and to explore the effect of the length of the linker in a target with a large binding site such as BACE-1. The incorporation of an aromatic ring within the linker, i.e.…”

Chemical and Pharmacological Studies on Enantiomerically Pure p‐Methoxytacripyrines, Promising Multi‐Target‐Directed Ligands for the Treatment of Alzheimer’s Disease

“…The inhibitory action of the single enantiomers at 50 mm was in the same range as propidium (89.8 %) [37] and bis (7)tacrine (71.2 %). [38] It should also be noted that tacrine, as well as other marketed drugs for the treatment of AD such as galanthamine and rivastigmine, does not show any significant antiaggregating properties (inhibition < 10 %).…”

Shogaol–huprine hybrids: Dual antioxidant and anticholinesterase agents with β-amyloid and tau anti-aggregating properties

“…Thus, in each model Trp286 was arranged to reflect one of the three major conformations found upon inspection of the available X-ray crystallographic structures. 26 A series of hybrids differing in the number of methylene units present between the huprine and shogaol units were docked in the hAChE models. On the basis of docking calculations, a preferential binding to the hAChE model in which Trp286 retains the orientation found in the AChE-propidium complex (PDB ID 1N5R) in conjunction with a chain of eight carbon atoms for the tether in the shogaol-huprine hybrids (i.e.…”

“…Since Trp286 can adopt three main conformations in the peripheral binding site, three models were built up by reorienting the side chain of Trp286 as found in the X-ray structures of the AChE complexes with propidium, bis(7)-tacrine and syn-TZ2PA6 (PDB ID: 1N5R, 2CKM and 1Q83, respectively). 26 These models were energy minimized using the AMBER force field. 51 Docking of AChE inhibitors was performed using the rDock program.…”