Dual-function triazole-pyridine derivatives as inhibitors of metal-induced amyloid-beta aggregation

Abstract

Dysregulated metal ions are hypothesized to play a role in the aggregation of the amyloid-β (Aβ) peptide, leading to Alzheimer's disease (AD) pathology. In addition to direct effects on Aβ aggregation, both Cu and Fe can catalyze the generation of reactive oxygen species (ROS), possibly contributing to significant neuronal toxicity. Therefore, disruption of metal-Aβ interactions has become a viable strategy for AD therapeutic development. Herein, we report a new series of dual-function triazole-pyridine ligands [4-(2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethyl)morpholine (L1), 3-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)propan-1-ol (L2), 2-(4-(pyridin-2-yl)- 1H-1,2,3-triazol-1-yl)acetic acid (L3), and 5-(4-(pyridin-2-yl)-1H-1,2,3- triazol-1-yl)pentan-1-amine (L4)] that interact with the Aβ peptide and modulate its aggregation in vitro. Metal chelation and Aβ interaction properties of these molecules were studied by UV-vis, NMR spectroscopy and X-ray crystallography. In addition, turbidity and transmission electron microscopy (TEM) were employed to determine the anti-aggregation properties of L1-L4. All compounds demonstrated an ability to limit metal-induced Aβ aggregation. Overall, our studies suggest the utility of the triazole-pyridine framework in the development of chemical reagents toward inhibitors for metal-triggered Aβ aggregation.