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

Abstract

A series of multi-target-directed ligands are described that bind Cu, act as antioxidants, modulate Aβ peptide aggregation, and abolish Aβ toxicity in primary neurons.

A Metallo Pro‐Drug to Target CuII in the Context of Alzheimer's Disease

“…In contrast, Cu II (Aβ) aggregates resemble more proto-fibrils, with aggregates of shorter less defined fibrillary structure, the impact of Cu(II) on aggregates morphology being in line with recent reports. [27b-d] In presence of 1 + , dense islets of fibres are observed, reminiscent of what was obtained with Mn(II) type fibrils, while in presence of LH only, apo-type are observed. These observations are consistent with the swapping process in the case of Cu(Aβ) + 1 + .…”

“…[2b, 27] Hence we probe the activity of 1 + and LH on the Cu(II)-mediated formation of small Aβ aggregates. The kinetic monitoring of Aβ aggregation has been performed using the classical ThT fluorescence assay, where ThT is a dye that acquires a strong fluorescence upon binding to fibrillary β-sheet structure (Figure 4).…”

Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

“…[55][56][57][58] However, in the presence of Cu, just oxygenating Ab may not entirely block its brillation because Cu can still promote protein aggregation by coordinating to Ab. Considering that Cu and Ab are two critical pathogenic factors of AD, 59,60 we envisioned that in situ synthesized bifunctional drug agent with Ab-oxygenating and Cu-chelating properties could effectively disassemble Ab-Cu aggregates in vivo.…”

A small bifunctional chelator that modulates Aβ42 aggregation

“…Although we did not test the antioxidant properties of L1, we expect the phenol moiety to exhibit ROS quenching effects as reported for similar derivatives. [43][44][45] The interaction of the ligand with Cu 2+ was probed using UV-vis spectroscopy. Upon addition of CuCl 2 to a solution of ligand, decreased intensity and shifts of the optical band at ca.…”