Medicinal Chemistry

Design, Synthesis and Biological Evaluation of 1-Phenyl-Ethanone Derivatives for Multi-Targeted Treatment of Alzheimer's Disease

Abstract

Meihao Liang, Wenhai Huang, Beibei Wang, Wenhua Wei, Chixiao Zhang, Zhimin Zhang and Zhengrong Shen

Alzheimer's disease (AD) is a progressive neurodegenerative disease leading to the irreversible loss of brain neurons and cognitive abilities. Multiple factors, such as acetylcholinesterase (AChE), metal ions and amyloid-β (Aβ) have been considered play an important role in the pathogenesis of AD. In this work, AChE and metal ions, both of which are also associated with the deposition of Aβ in the brain, were selected as targets simultaneously. 22 compounds were rationally designed by hybridizing AChE inhibitor rivastigmine and metal chelator 2-hydroxyacetophenone, in a hoping that these compounds could be as a substrate and inhibitor of AChE, while the subsequent enzymatic hydrolysis products by AChE could be as a metal ion chelator. Thus these 22 compounds were synthesized and their biological activities against AD were evaluated in vitro. The results showed that compound w8 presented the best inhibitory activity of AChE (IC50=31.9 μM), and the representing enzymatic hydrolysis products 7f exhibted the metal chelating function. Furthermore, both 7f and one of the targeted compound w15 could inhibit the aggregation of Aβ.