Importance of Hydrogen Bonding: Structure–Activity Relationships of Ruthenium(III) Complexes with Pyridine-Based Ligands for Alzheimer’s Disease Therapy

Alzheimer’s disease (AD) is
the most common form of dementia,
where one of the pathological hallmarks of AD is extracellular protein
deposits, the primary component of which is the peptide amyloid-β
(Aβ). Recently, the soluble form of Aβ has been recognized
as the primary neurotoxic species, making it an important target for
therapeutic development. Metal-based drugs are promising candidates
to target Aβ, as the interactions with the peptide can be tuned
by ligand design. In the current study, 11 ruthenium complexes containing
pyridine-based ligands were prepared, where the functional groups
at the para position on the coordinated pyridine
ligand were varied to determine structure–activity relationships.
Overall, the complexes with terminal primary amines had the greatest
impact on modulating the aggregation of Aβ and diminishing its
cytotoxicity. These results identify the importance of specific intermolecular
interactions and are critical in the advancement of metal-based drugs
for AD therapy.