Griess's Reagent-Based Azo Compounds Ameliorate Multifaceted Toxicity and Ferroptosis in Alzheimer's Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and a growing public health concern globally due to the lack of effective treatments. The primary pathological characteristics of AD include the accumulation of amyloid-β (Aβ) as extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau. Additionally, oxidative stress and neuroinflammation are implicated in the disease's pathogenesis. Developing therapeutic approaches to target multiple pathways or disease routes to address the complex pathological processes driven by Aβ remains challenging. In this context, multifunctional small molecules present a promising therapeutic strategy to address the multiple etiologies of AD. In this study, we designed and synthesized a series of multifunctional azo compounds (ACs) based on Griess's reagent. These compounds modulate amyloid aggregation, suppress oxidative stress, mitigate mitochondrial damage, and provide neuroprotection against Aβ-induced toxicity. Among the ACs, AC5 effectively prevents Aβ-induced ROS generation, as indicated by Nrf2 translocation, and exhibits anti-inflammatory activity by targeting inflammatory mediators, suppressing induced nitric oxide synthase (iNOS) expression, and reducing nitric oxide (NO) generation. Furthermore, AC5 effectively combats ferroptosis via modulating lipid peroxidation and restores the master regulator Gpx4 activity. Our findings suggest that AC5 is a promising therapeutic candidate for addressing the multifaceted pathogenesis of AD.