Design And Synthesis Of Leading Compounds About Double Target Alzheimer's Disease And The Study On Biological Activity

Alzheimer's disease?AD?is a neurodegenerative disease,which associated with age.Incidence of the disease increasing with age.The main clinical symptoms of AD include cognitive impairment,aphasia,executive and memory loss and death ultimately.The pathogenesis of the Alzheimer's disease still remain unclear.what's more,the symptoms of AD just only be relieved and can not be cured by existing drugs.There are more and more AD patients in the world.It is estimated that the number of AD patients will exceed 100million by 2050 in the world,which has brought serious affect in terms of both spiritual and economic aspects for patients and their families.Currently,there are only five drugs approved by the US Food and Drug Administration?FDA?for the treatment of AD,which four of them are cholinesterase inhibitors.Therefore,cholinesterase inhibitors are important for the study and treatment of AD.It is a basis that continue to research and develop new cholinesterase inhibitors.what's more,the research of new multi-target drug candidates has become the main research object.Therefore,a 2-carboxypiperazine-coupled tacrine-8-amino?hydroxy?quinoline derivatives were designed and synthesized based on 8-amino?hydroxy?quinoline.Here are some reasons for the design and synthesis of these target compounds.Firstly,piperazine could establish cation-?interaction with protonated nitrogen atoms,enhancing the inhibition to AChE through the binding of protonated nitrogen atoms with the mid-gorge site of AChE.Second,the carboxyl group on the piperazine ring could change the partition coefficient of the lipid-water of the compounds,affecting the ability of the amino or the hydroxy quinoline to complex the metal ions.We also explored the effects of carbon chain length,quinoline ring C6 substituents and C8 substituents on the activity of the compounds.The experimental results show that all of the two major classes of compounds 12 and 13 have inhibitory effects on cholinesterase activity and?-amyloid(A?_1-42)aggregation.When the carbon chain length is n=4 between piperazine and tacrine,the compound has the best inhibitory effect on cholinesterase activity and A?_1-42-42 aggregation,the best of which is compound 13 c,which the IC₅₀0 value for acetylcholinesterase?AChE?is 0.089?M,the IC₅₀0 value for butyrylcholinesterase?BuChE?is 0.06?M and the percentage of inhibition of A?_1-42-42 aggregation is 91.8%,which is much larger than that of the positive control curcumin?20?M,58.3%?.when a hydrogen atom which at the C6 position of the quinoline ring was substituted by a fluorine atom,the inhibitory effect of the compounds on cholinesterase activity and A?_1-42-42 aggregation will be reduced,greatly.The inhibition of cholinesterase activity and the inhibition of A?_1-42aggregation are not much different for the 8-hydroxyquinoline derivatives and the8-aminoquinoline derivatives when the carbon chain length is the same.These experimental results show that the 2-carboxypiperazine-coupled tacrine-8-amino?hydroxy?quinoline derivatives have both function that inhibiting not only cholinease activity,but also aggregation of A?_1-42.It is in line with the characteristics of double target cholinesterase inhibitors and is expected to be an effective leading compounds about double target Alzheimer's disease.These experimental results have created the base and pointed out the direction for the research works in the future.Therefore,subsequently,we are mainly to synthesis 2-carboxypiperazine-coupled tacrine-8-amino?hydroxy?quinoline derivatives,which the carbon chain length is n=4 and the 6-position substituent R is an electron-donating group or a hydrogen atom.Then to select the best double target cholinesterase inhibitor according to these biological activities of these compounds.