Synthesis And Bioactivity Of 4-N-aniline Quinoline Derivatives Containing 4-methylpiperidine Group

Alzheimer’s disease（AD）is a global problem,the number of patients is increasing year by year with the aging of the population,and the available drugs on the market are very limited,and most of them can only delay the deterioration of the disease and can not be cured completely.At present,the death rate of AD has ranked the fourth,only next to cancer,stroke and cardiovascular and cerebrovascular diseases.Because of its long course and high cost of treatment,patients and their families are suffering from both mental and economic suffering.In the face of this series of problems,the key to solve this problem is to find more effective ad drugsBecause the etiology and pathogenesis of AD are complex and unclear,the research of ad is very difficult.In order to solve this problem,it has become a consensus in academia that the mechanism of action of innovative drugs should be changed from single target to multi-target,so as to maximize the inhibition or elimination of pathogenic factors and achieve the best therapeutic effect.According to our research group for many years,4-N-anilinoquinoline compounds have good cholinesterase inhibitory activity.For this reason,we continue to use 4-N-anilinoquinoline as the core framework,and introduce 4-methylpiperidine pharmacophore to increase its biological activity,so as to synthesize two series of compounds,and then simultaneously to its cholinesterase inhibition activity,enzyme dynamics,replacement ability of propidium iodide,1,The scavenging activity of1-diphenyl-2-bitter hydrazine（DPPH）and the ability of metal chelation were evaluated.The molecular docking and blood-brain barrier（BBB）of DPPH were simulated and predicted.The test results show that all the tested compounds have certain anti-cholinesterase inhibitory activity,among which compounds 11a,11j,11k,11l,12f,12h,12l,and 12m have particularly anti-cholinesterase activity;And 11k and the12 series of tested compounds have PI replacement ability comparable to the control donepezill;11l and all 12 series of compounds have more than 80%DPPH clearance ability,most of which reached more than 90%,compound 12b and 12m are the best,both are 94%,and its activity is close to that of reference substance Vc.Except for compound 12b,the rest of the compounds undergo significant red shift after adding metal ions;Interestingly,11l and 12l containing 4-OH both chelate with Cu²⁺.Moreover,through BBB simulation,we can also find that most of the compounds meet Lipinksi principle;In addition,the molecular docking of compound 11j with1DX6 and 4BDS shows that compound 11j binds to 6 and 11 amino acids of the two target enzymes respectively,most of which belong to PAS and CAS sites.Through a series of pharmacological activity tests and evaluations,it has been shown that4-N-aniline quinoline compounds have scientific value for in-depth research.In the future,we will continue to modify and modify the structure of4-N-anilinoquinoline as the skeleton,and find the"one drug,multi-target"candidate drugs as early as possible,so as to provide a new way and new method for the multi-target strategy of AD treatment.