Design, Synthesis And Biological Evaluation Of Indan-1-one And Flavonoid Derivatives As AChE Inhibitors

Alzheimer's disease(AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition.To date,the enhancement of the central cholinergic function is the mainly effective approach,mainly by means of reversible acetylcholinesterase(AChE) inhibitors.Recent studies suggested that dual-binding inhibitors not only inhibited the hydrolysis of AChE toward ACh,but also prevented the aggregation of toxicβ-amyloid(Aβ).Moreover,some AChE inhibitors possess neuroprotective activity in vivo and in vitro.In recent years,there has been a growing interest in the search for potent AChE inhibitors.In continuring our research for dual-binding AChE inhibitors,some modifications were made on the the basis of 5,6-dimethoxy-2-(4-(pyrrolidin-1-ylmethyl) phenoxy)-2,3-dihydro-1H-inden-1-one.The length of the linker between the benzene ring and the tertiary amine was increased up to 2-4 methylene units;A carbonyl group was introduced within the linker chain;The oxygen atom between the indanone and benzene ring was replaced by =CH₂-NH;Indanone fragment was replaced by tacrine and acetophenone.35 indanone derivatives,8 tacrine derivatives and 7 acetophenone derivatives were synthesized and their structures were confirmed.The target compounds were assayed for rat AChE,human AChE and rat BuChE inhibition.Most of the compounds demonstrated potent AChE inhibitory activity and selectivity, among them,4 compounds demonstrated AChE activity with an IC₅₀ within 0-10nmol/L.To explore the possible binding conformation,a molecular modelling study of the optimum compound 2-67 was performed,and the result showed that the compound interacted well with both the catalytic and the peripheral binding sites.The neuroprotective effect of the representative compound 2-67 against H₂O₂-induced cell death was evaluated,and the result showed that the compound possessed obvious neuroprotective effect at various concentrations.Considering that benzyl piperidine moiety can interact with AChE at the catalytic site, and the aromatic ring of flavanoid may have the chance to interact with the PAS of AChE,various flavonoids(flavone,isoflavone,flavonone or chalcone) and N-benzyl piperidine were chosen as the two pharmacophoric moieties and linked with oxygen or alkoxyl group.Thus,21 flavanoid derivatives were designed,synthesized and evaluated for their AChE inhibition activity.Most of the target compounds demonstrated moderate AChE inhibitory activity.Among them,isoflavone derivatives were more potent than other series,and the most potent compound possessed an IC₅₀ of 0.093 nmol/L.