KCS

While the etiology of Alzheimer’s disease (AD), a fatal form of dementia, still remains elusive, multiple neuropathological factors, such as misfolded proteins (e.g. Aβ and tau), metal ions, and acetylcholinesterase (AChE) have been proposed to be involved in AD neuropathogenesis. Metal ions and AChE have been observed to be deposited with accumulated Aβ plaques; however, the correlation between all three factors (Aβ, metal ions and AChE) have yet to be elucidated. The interaction between two factors (Aβ and metal ions or AChE), has been studied and reported. Metal binding to Aβ have seen suggested to facilitate Aβ aggregation and generate reactive oxygen species.2 Inhibition of AChE, a serine protease that hydrolyzes the neurotransmitter acetylcholine (ACh), has been shown to temporarily reduce cognitive decline in addition to Aβ aggregation, due to inhibition of the peptide binding to the AChE peripheral site. Therefore, in order to target metal-associated Aβ species and AChE concurrently, a multifunctional small molecule containing bifunctionality (Aβ interaction and metal chelation) and AChE inhibitory activity was designed.4 Herein, the design, synthesis, and characterization of the hybrid will be presented. In addition, we will report the activities of our hybrid toward AChE inhibition with Aβ and/or metal ions as well as metal-free and metal-induced Aβ aggregation in the absence and presence of AChE.