Design, Synthesis And QSAR Study Of Indan-1-one Derivatives As AChE Inhibitors

Part â… : Design, synthesis and QSAR study of indan-1-one derivatives as AChE inhibitorsAlzheimer's disease (AD) has been one of the most severe health problems of the elderly. Acetylcholinesterase (AChE) inhibitors are the first and the most developed group of drugs approved for AD symptomatic treatment. Unfortunatedly, all the drugs used in clinic only showed modest effects. So we are interested in searching for new AChE inhibitors.The crystallographic structure of AChE exhibits that it contains peripheral anionic site and central site. It has been pointed out recently that AChE may be responsible for several noncatalytic actions besides hydrolysis Ach, such as: accelerating β-amyloid peptide deposition, and this function only related with the peripheral anionic site (PAS). Therefore, molecules able to interact both central and peripheral binding sites may prevent the catalytic and noncatalytic actions of AChE. Following this reasoning, 5,6-dimethoxy-indan-1-one from donepezil (interacting with the peripheral site of AChE), dialkylbenzylamine from rivastigmine (interacting with the centric site of AChE) were chosed as the two pharmacophoric moieties, and linked with O, =CH and CH₂. Thus, series of 2-phenoxy-indan-1-one, 2-benzylidene-indan-1-one and 2-benzyl-indan-1-one derivatives were designed, synthesized and tested for their AChE inhibitory activity. Most of these derivatives exhibited high AChE inhibitory activity in vitro, and the IC50 values of three compounds were closed to that of Donepezil. The research of their bioactivity in vivo is going on.Compound 53 was picked out to carried out molecular docking study to understand the binding mode in AChE, and results showed that it made principal interactions along the active gorge of the enzyme through four major functional groups: phenyl and oxygen of indan-1-one, phenyl of benzyl group, charged nitrogen of pyrrolidine. On the basis of this founding, the CoMFA and CoMSIA models of 2-phenoxy-indan-1-one derivatives were built and explain the structure-activity relationships in detail. These results will give us some useful indications in the design of new drugs.Part II: Studies on the synthesis of DonepezilDonepezil was the most widely used AChE inhibitor in clinic. To study and improve the method of producing Donepezil, a novel and efficient method was developed to synthesize N-benzyl-4-formyl-piperidine, key intermediate of Donepezil. N-Benzyl -4-piperidone was reacted with dimethyloxo sulfonium methylide to get epoxide, followed by rearrangement in the presence of magnesium bromide etherate to give the aldehyde in high yield. Then it was condensed with 5,6-dimethoxy-indan-l-one to yield a,P-unsaturated ketone, followed by selective hydrogenation with 5% Pd/C and hydrochlorination to yield Donepezil. This synthesis route avoids using expensive reagents such as n-BuLi, LDA, and there is no need to use column chromatograph in all steps.