title: 1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BuChE, and amyloid-β aggregation crossing the blood-brain barrier.
abstract: Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BuChE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid β fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BuChE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC₅₀=90 nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BuChE and enhances the fibril destruction.
authors: Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany.
authors: Michaela
authors: M
authors: Prinz
authors: Sülünay
authors: S
authors: Parlar
authors: Gülşah
authors: G
authors: Bayraktar
authors: Vildan
authors: V
authors: Alptüzün
authors: Ercin
authors: E
authors: Erciyas
authors: Adyary
authors: A
authors: Fallarero
authors: Daniela
authors: D
authors: Karlsson
authors: Pia
authors: P
authors: Vuorela
authors: Malgorzata
authors: M
authors: Burek
authors: Carola
authors: C
authors: Förster
authors: Ezgi
authors: E
authors: Turunc
authors: Guliz
authors: G
authors: Armagan
authors: Ayfer
authors: A
authors: Yalcin
authors: Carola
authors: C
authors: Schiller
authors: Kristina
authors: K
authors: Leuner
authors: Manuel
authors: M
authors: Krug
authors: Christoph A
authors: CA
authors: Sotriffer
authors: Ulrike
authors: U
authors: Holzgrabe
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells; D057809:HEK293 Cells; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D006835:Hydrazones; D017382:Reactive Oxygen Species; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: AChEIs; AD; APOE; APP; Acetylcholinesterase (AChE); Alzheimer; Alzheimer’s disease; Amyloid β; BuChEI; Butyrylcholinesterase (BuChE); COX; DCF; DCF-DA; GSK; HFIP; LP; MDA; MMP; NSAID; PSA; ROS; TBA; TEER; ThT; Thioflavin T; acetylcholinesterase inhibitors; amyloid precursor protein; apolipoprotein; butyrylcholinesterase inhibitor; cEND; cerebral capillary endothelial; cyclooxygenase; dichlorofluorescein; dichlorofluorescin diacetate; glycogen-synthasekinase; hexafluoroisopropanol; lipid peroxidation; log of the brain/blood distribution ratio; log of the permeability–surface area coefficient; logBB; logPS; malondialdehyde; mitochondrial membrane potential; non-steroidal anti-inflammatory drugs; polar surface area; reactive oxygen species; thiobarbituric acid; thioflavin T; transepithelial electrical resistance