Design, Synthesis And Structure-Activity Relationships Study Of Flavonoids As AChE Inhibitors

Alzheimer's disease (AD), which is also called early aged dementia, is a neurodegenerative disorder characterized by a progressive impairment of cognitive function. AD is also one of the most common causes of mental deterioration in elderly people. Acetylcholinesterase (AChE) inhibitors are the first and the most developed group of drugs approved for AD symptomatic treatment. Unfortunately, all the drugs used in clinic showed insufficiency. So we are interested in searching for new AChE inhibitors,The crystallographic structure of AChE exhibits that it contains central site and peripheral site. In our prophase work, 5,6-dimethoxy-indan-l-one from donepezil (interacting with the peripheral site), dialkylbenzylamine from rivastigmine (interacting with the central site) were chosen as the two pharmacophoric moieties and linked with O, CH₂ and CH, thus, three series of indanone derivatives were synthesized and most of these derivatives exhibited high AChE inhibitory activity in vitro.On the basis of our prophase work, modification of the indan-1-one part of the indanone derivatives v/ere taken to investigate the contribution to the AChE inhibitory activity of this part. Benzofuran-3-one, benzopyran-4-one, benzodihydropyran-4-one and 2-hydroxyacetophenone were chosen to replace the indan-1-one of the indanone derivatives, thus, a series of new flavonoid derivatives were synthesized, containing aurones, dihydroaurones, chalcones, flavones, flavanones and isoflavones. All these derivatives maintain the four functional groups interacting with AChE, which are phenyl, carbonyl, benzyl and alkylamine. Therefore, they should be able to interact with both central and peripheral binding sites of AChE, through which they could prevent not only the hydrolysis of ACh, but also β-amyloid peptide deposition caused by AChE.Totally, thirty-six target compounds were prepared, containing aurone, dihydroaurone,chalcone,flavone,flavanone and isoflavone derivatives each six, which are all new compounds. All the structures were confirmed by ¹HNMR and IR.Thirty-six flavonoid derivatives were tested for their AChE inhibitory activity in vitro. Most of these derivatives exhibited high AChE inhibitory activity, and the IC50 values ofthree compounds were lower than that of Donepezil. Therefore, these compounds are very promising lead compounds for the treatment of AD.On the basis of AChE inhibitory activity of the target compounds, structure-activity relationships discussion was taken, which will give us some useful information in the design of new drugs.