Multi-target-directed phenol-triazole ligands as therapeutic agents for Alzheimer's disease

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.