Design,Synthesis And Biological Evaluation Of Acetylcholinesterase Inhibitors Based On Acridine Moieties

Aim:Alzheimer’s Disease（AD）is a neurological disorder characterized by the damage of cognitive function which has caused great loss to the society.As the aging of population,the prevalence of AD is getting higher,calling for more effective anti-AD drugs.Acetylcholinesterase（ACh E）is an established target for AD.It breaks down acetylcholine（ACh）and accelerates the aggregration of Amyloidβ（Aβ）.It has two important sites,namely Catalytic Anionic Site（CAS）and Peripheral Anionic Site（PAS）.Previously,a wide range of dual-site ACh E inhibitors were reported,but few of them finally appear on the market.In this research,the aim is to acquire potent dual-site ACh E inhibitors based on acridine moieties.Method:Based on the structure of ACh E,molecules composed of acridine and benzylamine moieties linked by different linker lengths were designed.In the CADD phase,target molecules were docked into ACh E and butyrylcholinesterase（BCh E）,respectively.During the synthesis of the target compounds,simple compounds,such as benzaldehyde,2-chlorobenzoic acid,aniline,phenol andα,ω-diamines,were used as starting materials.Through condensation,ring closure,etherification and reductive amination,the building blocks were synthesized.The building blocks were combined to give target compounds.Finally,their activities against ACh E and BCh E were tested and structure-activity relationship（SAR）was analyzed.Result:CADD results showed that most molecules,especially 1e and1f whose linker length equals to 6 and 7 respectively,bind to both CAS and PAS of ACh E in preferable conformations;all of them showed moderate interaction with BCh E.9 inhibitors and 1 positive control drug were synthesized and their structures were confirmed with NMR and MS.The activities of target compounds against ACh E increased with the increasing of linker length,with compound 1e（linker length=6）showing the highest activity(IC₅₀=17.19±1.48 n M).In addition,all compounds showed moderate activities against BCh E.Conclusion:In this research,a series of high-affinity ACh E inhibitors were acquired.The SAR of acridine-based ACh E inhibitors was systematically evaluated.The CADD results partially aligns with activity results.The present study is of considerable importance as it provides insights into the design and development of potent acridine-based ACh E inhibitors.