Protection against Amyloid-β Aggregation and Ferroptosis/Oxytosis Toxicity by Arylpyrazolones: Alzheimer’s Disease Therapeutics

Alzheimer’s disease (AD) incurs heavy costs for both the population and health systems. Nevertheless, the drugs available only provide minimal symptomatic management without much impact on the patients’ quality of life. The multifactorial character of AD suggests that the development of new therapies modulating multiple biological targets contributing to disease progression will more efficiently treat the disease. The success of therapies targeting amyloid-beta oligomers suggests this is a valid approach for the development of more efficacious therapies for AD. Here, we report the design and evaluation of a series of arylpyrazolone compounds for their activity against Aβ aggregation toxicity and oxidative stress. The lead compound (1) has an EC₅₀ value of 270 nM, good blood-brain barrier permeation in vivo and promising bioavailability. This study demonstrates the potential of these arylpyrazolones as novel, and potentially more effective, multifactorial therapies for AD.