Design, Synthesis And Bio-evaluation Of Novel Potential Dual-binding Inhibitors Of Acetylcholinesterase And β-secretase

Abstract:Alzheimer’s disease (AD), also known as presenile dementia, is the most common form of aging dementia. Because the pathogenesis of AD is complicated and related to the abnormality and dysfunction of multiple systems, the efficacy brought by singular target hitting medicine is unsatisfactory. Current study is aimed at discovering novel potential multi-target-directed ligands to modulate relavent signal paths or target receptors and obtaining high efficiency and low-toxicity dual-binding inhibitors of acetylcholinesterase and β-secretase.In this study, corydaline is choosed as a lead compound, which was extracted and separated from Chinese herb medicine and used for the treatment of memory dysfunction in folk medicine reported the presence of benzylisoquinoline alkaloids with anti-AChE activity. According to the research of inhibitor binding pocket in3D structure of acetylcholinesterase and β-secretase with relavent ligands, and research of chemical structure of corydaline, we open the B circle of lead compound and design the key intermediate to7-amino-l,4-dihydro-2H-isoquilin-3-one, which acts as central aromatic moiety in final virtual screening molecules. The other two parts of aromatic ring are linked with the central part with amido bond. Such derivates with three parts of aromatic moieties and sufficient hydrogen bond donor and acceptor of amido bond are able to interact with active sites in acetylcholinesterase and β-secretase, including catalytic site, peripheral site and central channel active site of acetylcholinesterase, and catalytic site of β-secretase.On the basis of results of virtual screening, synthetic route of key intermediate is designed by the method of retrosynthetic analysis.14intermediates and derivates are synthesized, of which the structure characterization are confirmed by1H-NMR. All the compounds are structural novel.Acetylcholinesterase in vitro assay is performed by employing the method of Ellman method. The inbihition activity of compound12b4(IC5o=10.95pM) is316times as high as donepezil (IC50=3.46nM), and all the other newly synthetic compounds are more effective than positive control inhibitor. The results of bio-evaluation demonstrate that all the newly synthetic compounds are worthy of further modification for their high efficacy of inhibiting AChE connected with AD.The whole paper contains58figures,11tables and58references in total.