Abstract
Fourteen different ligands have been synthesized with two covalently linked 8‐hydroxyquinoline motifs that favor metal complexation. These bis‐chelators include different bridges at the C2 positions and different substituents to modulate their physicochemical properties. They can form metal complexes in a ratio of one ligand per metal ion with Cu^II^ and Zn^II^, two metal ions involved in the formation of amyloid aggregates of the toxic Aβ‐peptides in the Alzheimer disease. The apparent affinity of all bis‐8‐hydroxyquinoline ligands for Cu^II^ and Zn^II^ are similar with log__K__ ≈16 and log__K__ ≈13 and are 10 000 times more efficient than for the corresponding 8‐hydroxyquinoline monomers. Their strong chelating capacities allow them to inhibit more efficiently than the corresponding monomers the precipitation of Aβ‐peptides induced by Cu^II^ and Zn^II^ and also to inhibit the toxic formation of H~2~O~2~ due to copper complexes of Aβ. The best results were obtained with a one‐atom linker between the two quinoline units. X‐ray analyses of single‐crystals of Cu^II^, Zn^II^ or Ni^II^ complexes of 2,2′‐(2,2‐propanediyl)‐bis(8‐hydroxyquinoline), including a one‐atom linker, showed that all heteroatoms of the bis‐8‐hydroxyquinoline ligand chelate the same metal ion in a distorted square‐planar geometry. The Cu^II^ and Zn^II^ complexes include a fifth axial ligand and are pentacoordinated.