Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer's disease
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| Authors: | Jones, MR; Mathieu, E; Dyrager, C; Faissner, S; Vaillancourt, Z; Korshavn, KJ; Lim, MH; Ramamoorthy, A; Yong, VW; Tsutsui, S; Stys, PK; Storr, T |
| Year: | 2017 |
| Journal: | Chem. Sci. 8: 5636-5643 Article Link (DOI) PubMed |
| Title: | Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer's disease |
| Abstract: | Alzheimer's disease (AD) is a multifactorial disease that is characterized by the formation of intracellular neurofibrillary tangles and extracellular amyloid-beta (A beta) plaque deposits. Increased oxidative stress, metal ion dysregulation, and the formation of toxic A beta peptide oligomers are all considered to contribute to the etiology of AD. In this work we have developed a series of ligands that are multi-target-directed in order to address several disease properties. 2-(1-(3-Hydroxypropyl)-1H-1,2,3-triazol-4-yl) phenol (POH), 2-(1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl) phenol (PMorph), and 2-(1-(2-thiomorpholinoethyl)-1H-1,2,3-triazol-4-yl) phenol (PTMorph) have been synthesized and screened for their antioxidant capacity, Cu-binding affinity, interaction with the A beta peptide and modulation of A beta peptide aggregation, and the ability to limit A beta(1-42)-induced neurotoxicity in human neuronal culture. The synthetic protocol and structural variance incorporated via click chemistry, highlights the influence of R-group modification on ligand-A beta interactions and neuroprotective effects. Overall, this study demonstrates that the phenoltriazole ligand scaffold can target multiple factors associated with AD, thus warranting further therapeutic development. |
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