title: sym-Triazines for directed multitarget modulation of cholinesterases and amyloid-β in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a complex neurodegenerative disorder marked by numerous causative factors of disease progression, termed pathologies. We report here the synthesis of a small library of novel sym-triazine compounds designed for targeted modulation of multiple pathologies related to AD, specifically human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and Aβ aggregation. Rational targeting of AChE was achieved by the incorporation of acetylcholine substrate analogues into a sym-triazine core in either a mono-, di-, or trisubstituted regime. A subset of these derivatives demonstrated improved activity compared to several commercially available cholinesterase inhibitors. High AChE/BuChE selectivity was characteristic of all derivatives, and AChE steady-state kinetics indicated a mixed-type inhibition mechanism. Further integration of multiple hydrophobic phenyl units allowed for improved β-sheet intercalation into amyloid aggregates. Several highly effective structures exhibited fibril inhibition greater than the previously reported β-sheet-disrupting penta-peptide, iAβ5p, evaluated by thioflavin T fluorescence spectroscopy and transmission electron microscopy. Highly effective sym-triazines were shown to be well tolerated by differentiated human neuronal cells, as demonstrated by the absence of adverse effects on cellular viability at a wide range of concentrations. Parallel targeting of multiple pathologies using sym-triazines is presented here as an effective strategy to address the complex, multifactorial nature of AD progression.
authors: Department of Physical and Environmental Sciences, University of Toronto Scarborough , 1265 Military Trail, Toronto, Ontario M1C 1A4, Canada.
authors: Anthony J
authors: AJ
authors: Veloso
authors: Devjani
authors: D
authors: Dhar
authors: Ari M
authors: AM
authors: Chow
authors: Biao
authors: B
authors: Zhang
authors: Derek W F
authors: DW
authors: Tang
authors: Hashwin V S
authors: HV
authors: Ganesh
authors: Svetlana
authors: S
authors: Mikhaylichenko
authors: Ian R
authors: IR
authors: Brown
authors: Kagan
authors: K
authors: Kerman
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D000544:Alzheimer Disease; D000682:Amyloid / Q000187:drug effects* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects; D014227:Triazines / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D014227:Triazines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase