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-beta (A beta) peptide, leading to Alzheimer's disease (AD) pathology. In addition to direct effects on A beta aggregation, both Cu and Fe can catalyze the generation of reactive oxygen species (ROS), possibly contributing to significant neuronal toxicity. Therefore, disruption of metal-A beta 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 A beta peptide and modulate its aggregation in vitro. Metal chelation and A beta 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 A beta aggregation. Overall, our studies suggest the utility of the triazole-pyridine framework in the development of chemical reagents toward inhibitors for metal-triggered A beta aggregation.