Dual-function triazole–pyridine derivatives as inhibitors of metal-induced amyloid-β 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.

Crystal structure of catena-poly[[[dichloridocopper(II)]-{μ-tert-butyl N-methyl-N-[4-(6-{[4-(pyridin-2-yl-κN)-1H-1,2,3-triazol-1-yl-κN 3]methyl}-1,3-benzothiazol-2-yl)phenyl]carbamato}] acetonitrile monosolvate]

“…tert-butyl methyl[4-(6-{[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]methyl} benzo [d]thiazol-2-yl]phenyl}carbamate (L). Indeed integrating the N-binding from the triazole moiety in the binding site of a chelator has been shown to be a successful approach (Jones et al, 2012(Jones et al, , 2017. Compared to these seminal works, the additional aryl-benzothiazole moiety in compound L is expected to enhance the ability of the chelator to interact with amyloid aggregates and thus to retrieve deleterious Cu II ions ISSN 2056-9890 from A fibrils.…”

“…These bond lengths are similar to those observed for a related complex, viz. dichloro-(4-{2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethyl}morpholine)copper(II) (Jones et al, 2012).…”

8-Hydroxyquinoline Schiff-base compounds as antioxidants and modulators of copper-mediated Aβ peptide aggregation

“…TEM grids were prepared following previously reported methods. 9,76 In order to 240 increase hydrophilicity, the Formvar/Carbon 300-mesh grids (Electron Microscopy 241 Sciences) were glow discharged in a vacuum for 15 seconds. Drops of samples (10 L) 242 were placed onto a sheet of parafilm and the TEM grid was laid on the drop for 5 243 minutes.…”

“…2,[6][7] The mechanism underlying the causes and progression of AD is 10 subject to enormous research efforts, and the search for new and effective therapies is 11 justified by the lack of effective treatment options. [8][9] 12 Diagnosis of AD, as opposed to other forms of dementia, requires post-mortem 13 examination of the brain to determine the severity of neuropathological hallmarks of the 14 disease; amyloid-beta (A) plaques and neurofibrillary tangles. Neurofibrillary tangles 15 are intracellular fibrillar aggregates of oxidatively-modified and hyperphosphorylated 16 microtubule-associated protein tau.…”

“…To achieve complete dissolution of the peptide, sonication for 1 minute followed 203 by a 30 second pause was repeated twice. 9 A 20 mM HEPES buffer solution containing 204 150 mM NaCl was prepared and treated with Chelex in deionized water at pH 6. Substrate kit was used to visualize the A species using a FUJIFILM Luminescent 235…”