Strategies for developing flavonoids with multiple reactivities against pathological features in Alzheimer’s disease

The etiology of Alzheimer’s disease (AD) is still unknown because of its complicated nature associated with various pathological components, including free radicals, acetylcholinesterase, and metal-free and metal-bound amyloid-beta. Thus, chemical reagents with modulating reactivities against multiple pathogenic factors are necessary for advancing our understanding of the complex pathogenesis. Here we report rational strategies for developing flavonoids that can control multiple pathological elements found in the brains of AD patients. Our investigations employing a series of flavonoids illuminated structural features critical for regulatory reactivities against desired targets. Moreover, the most promising flavonoid with multiple functions was developed based on our complete structure–activity relationship. Mechanistic studies confirmed that such versatile reactivities of the flavonoid are achieved by its redox potential and direct interactions with pathogenic factors. Overall, our studies demonstrate the feasibility of devising small molecules as multifunctional chemical reagents against pathological features found in AD.