Hydrazines as Potential Anti‐amyloidogenic Agents

Several neurodegenerative diseases are characterized by the formation of highly organized and extremely stable fibrillar aggregates as well as their soluble oligomers. One of the approaches to develop therapeutics for these diseases is to destabilize these aggregates and inhibit their formation. Our earlier work with hydrazones has resulted in strong inhibitors towards the self‐assembly of Alzheimer's disease's (AD) amyloid beta (Aβ) peptide. Due to the possible metabolic instability of the hydrazones, which may result in the reformation of their synthetic precursors, these studies were extended to the effect of the precursors, such as phenylhydrazines and benzaldehydes on the self‐assembly of amyloid beta. In our present work we describe the application of over 30 hydrazone precursor molecules in the inhibition of Aγ self‐assembly including fibril and oligomer formation, as well as, in the disassembly of preformed Aγ aggregates. As possible multifunctional scaffolds, the compounds were also assayed for antioxidant activity, which may result in potential drug candidates that can interfere with multiple pathways in the development of AD. The data indicate that phenylhydrazines are promising multifunctional agents for further drug development in AD.