Design,Synthesis And Activity Evaluation Of Inhibitors Of Beta-Secretase(BACE1)Associated With Alzheimer's Disease And Synthesis And In Vitro Evaluation Of Scutellarein Methyl Derivatives

Section 1.Design,Synthesis and Biological Evaluation of Inhibitors of BACE1 Associated with Alzheimer's DiseaseAlzheimer's Disease is a neurodegenerative disease,which often occurs in the elderly population.The clinical manifestations of the disease include deterioration of cognitive and memory deterioration,activities of daily living,various neurological and psychiatric symptoms and behavioral disorders.At present,the main drugs used for the treatment of AD are acetylcholinesterase inhibitors.However,it can only improve the patient's cognitive ability to alleviate the condition,instead of basically cure the disease.Numerous extracellular amyloid plaques in the brain,the main component of which are?-amyloid peptides(A?),are an important pathological feature of AD.The hydrolysis of beta precursor like protein(APP)gives A? and beta secretory enzyme is the key rate limiting enzyme in the formation of A?.Therefore,BACE1 inhibitors have become a hot spot in the prevention and treatment of AD drug.Because of the complex of pathogenesis of AD,the development direction of the therapeutic drug has turned to two targets or multiple targets instead of limiting to a single target.The high oxygen consumption in the brain and the loss of endogenous active substances of AD patients makes the central nervous system vulnerable to the damage of free radicals and free radicals can cause deposition of A?.In this paper,BACE1 and free radicals are selected as targets.BACE1 inhibitors and free radical scavenging agents reported in the literature are used in molecular hybridization to design amino heterocyclic compounds.Computer-aided drug design(CADD)is used to build a pharmacodynamic model of BACE1 inhibitors,which is used to predict the activity of compounds.The compounds were not reported in the literature.The structures of all the compounds were confirmed by 1H-NMR and LC-MS.We used the fluorescence resonance energy transfer method to determine the BACE1 inhibition activity of the synthesized compounds in molecular level in vitro and compared the antioxidant capacity of each compound by DPPH radical scavenging,ABTS+·free radical scavenging method and Fe3+ reducing method in vitro.Compounds D-1 and D-5 not only had good inhibition ability of BACE1,but also showed the ability of free radical scavenging.In addition,through the comparison of the results of the evaluation and the results of the pharmacophore prediction,it is found that the pharmacophore model has certain reliability,which is of guiding significance for the design of the compound.In this paper,the structure activity relationship of inhibiting BACE1 activity of the synthesized compounds was summarized according to the results of in vitro activity evaluation and molecular docking.The binding mode of compound and BACE1 was explored.The analysis results of this paper lay the foundation for further optimization of the active compounds.Section 2.Synthesis and in vitro evaluation of scutellarein methyl derivativesCardiovascular disease is a serious hazard to human health,with high incidence,high disability rate,high recurrence rate,high mortality and complications.Traditional Chinese medicine has been used in clinic for years,many of them have good pharmacological activity on cardiovascular and cerebrovascular diseases,and can be used as potential source of drug discovery.Breviscapine(breviscapine)is a flavonoid extracted from Erigeron breviscapus(vant)Hand-Mazz.,constituted of scutellarin(>95%)and Erigeron Corydaline,the main active ingredient is scutellarin.It is widely used in the treatment of ischemic cardiovascular and cerebrovascular diseases and sequelae of apoplexy in clinic.However,the solubility of scutellarin is poor,the bioavailability of oral is very low,and its metabolism in vivo is very fast,so the clinical application of scutellarin has been limited.Scutellarin first hydrolyzed into scutellarein in the intestinal after oral administration,which is the main form of its absorption by the body,and then metabolized to methylation and glucuronidation and sulfation and glucuronidation of DNA material.A large number of 6-O-methyl-scutellarein is detected in urine which may play a major role during the drug action of scutellarin.Based on the above analysis,in order to investigate the in vitro activity and physical and chemical properties of 6-O-methyl-scutellarein and other hydroxylated products,and to summarize the relationship between the phenolic hydroxyl group and activity,we synthesized 8 scutellarein derivatives via semi synthesis method and tested their anticoagulant activity,solubility and interactions with bovine serum albumin.The results showed that 6-O-methyl-scutellarein had better anticoagulant activity and solubility.All compounds showed strong binding capacity with bovine serum albumin.This study laid a foundation for further study of the scutellarein methyl derivatives and further study on pharmacological and pharmacodynamic characteristics of scutellarin in the treatment of cardiovascular and cerebrovascular diseases.