Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia

Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-β (Aβ), and metal-bound Aβ that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aβ, leading to chemical modifications of the Aβ peptides to form covalent adducts that alter the aggregation of Aβ. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.