Design,Synthesis And Structure-activity Investigation Of Ferulic Acid Derivatives In InhibitingAChE

Alzheimer's disease is a common degenerative disease of the central nervous system(CNS)in the elderly.Although there are many theories about the pathogenesis of Alzheimer's disease,the treatment of Alzheimer's disease(AD)is mainly based on acetylcholinesterase inhibitor(AChEI).But at present,some disadvantages such as hepatotoxicity,cardiovascular adverse reactions and gastrointestinal reactions exist in AChEI in the clinic application.Therefore,it is of great research value and prospect to seeking for new acetylcholinesterase inhibitors.Seeking for new drugs against Alzheimer's disease from natural products is one of the intensive investigate topics in recent years.The research on Chinese traditional medicine prescription,single herb medicine,or the components of them are all including.In previous studies a large number of derivatives.of chalcone derivatives with tertiary amine groups were found with good effects in inhibiting acetylcholinesterase(AChE),which was suspected that the inhibitory effects were relative with tertiary amine group and ?,?-unsaturated ketone group in chalcone scaffold.In order to further confirm and develop this scientific finding,we selected ferulic acid as the investigate object which possesses ?,?-unsaturated ketone group as the same of chalcones.Ferulic acid is a bioactive ingredient widely existing in plant or Chinese medicinal herbs,such as chaff,Ligusticum wallichii,rhizoma cimicifugae and Angelica sinensis.Ligusticum wallichii can treat headache and rheumatism,Rhizoma cimicifugae is suitalbe for the treatment of Headache fever,typhus and depression of Qi,while Angelica sinensis had the effects in remedying and regulating blood.Although these medicinal herbs had different effects for the treatment of diseases,they contained the same ingredient-ferulic acid,which may have some contribution to its efficacy.Alzheimer's diseases is a neurological disease in the brain,and.the normal maintenance of neurological function depends on the supply of the blood.Therefore,the theory of traditional Chinese medicine in the "invigorating splenic Yang","remedy blood" and "regulate blood" may play a certain guiding role in the treatment of Alzheimer's diseases.But these herbs are very complex,and their active ingredients(such as flavonoids and organic acids)have low biologicalactivity and wide range of effects.So,the structural modification of natural products may be one of the approaches to develop new Chinese medicine.Compared with the study of Chinese medicine decoction or single traditional Chinese medicine,modified natural products would provide benefit for the qualitative and quantitative investigation to achieve the level of international standards.This paper is divided into the following parts:1 Synthesis of ferulic acid derivatives and chemical structure characterizationIn this chapter,28 ferulic acid amide derivatives with different carbon chain length were synthesized(2c-8c,compound 2b-8b,2d-8d,2e-8e).On the basis of this,four compounds of ferulic acid and ferulic acid ethyl ester were synthesized respectively by selecting the compounds with strong inhibitory effect on acetylcholinesterase in the subsequent biological activity determination.The yield of the synthetic process was high,and the purity of the compounds was determined by HPLC.2 Determination of ferulic acid derivatives in inhibiting AChE,Bu ChE and structure activity relationship investigationIn this chapter,the effect of ferulic acid and ferulic acid,amide ethyl tertiary amine derivatives in inhibiting acetylcholinesterase,butyrylcholinesterase,carboxylesterase,aminopeptidase were determined,and enzyme kinetics,molecular docking experiment were conducted.The results show that the synthesis of ferulic acid amide derivatives with high specificity in inhibiting cholinesterase,the bioactivity in inhibiting AChE were influenced by the tertiary amine species,the length of carbon chain.If the amide group was removed,or replaced by the ethyl ester,the inhibitory activity was decreased to some extent.Enzyme kinetics experiments showed that the compound 6d had a mixed type of competitive and non competitive inhibition against AChE.Molecular docking experiments show that compound 6d has three bind sites with acetylcholinesterase,which is the nitrogen atom on the tertiary amine group,and the two benzene rings on ferulic acid benzamide,respectively.3 The interaction of compound 6d and other compounds in inhibiting AChEIn this chapter,we mainly investigated the interaction of ferulic acid tertiary amine derivative 6d with other compounds in inhibiting AChE.The inhibitory effects of combination of compound 6d and other compounds with the same structure scaffold was stronger than that of either of them alone.When the compound 6d was combined with the parent compound ferulic acid amide,the effect in inhibiting AChE was not decreased.If compound 6d was combined with chalcone derivatives with inhibitory AChE effects,the effect was stronger than that of compound 6d alone.However,the inhibitory effect of compound 6d on AChE was significantly weaker than that of compound 6d combined with chalcone derivative with no inhibitory effect on AChE.So we speculate that if the bioactive compounds combined with other compounds with different structure and no bioactivity,the bioactivity will be significantly decreased.4 Determination of basic physicochemical properties of compound 6d and preliminary pharmacokinetic study in miceThe oil-water partition coefficient(logP)of compound 6d is 1.77,which is the appropriate logP for an oral drug.The pKa was 7.14,which suggested compound 6d was a weak base.It is stable in the solution of pH 2-10.It is stable in thermal condition with few hygroscopicity.Preliminary pharmacokinetic studies in mice showed that the compound 6d showed a one compartment model with lag time in vivo.It can penetrate the blood brain barrier with a rapid absorption and short half-life.