Design And Synthesis Ligustrazine Derivatives With Cholinesterase Inhibitory Activity And Cytoprotective Activity Based On The Combination Of Traditional Chinese Medicine Chemistry

Alzheimer's is a degenerative disorder of the central nervous system characterized by progressive cognitive dysfunction and behavioral impairment,which is premature and elderly.The main clinical manifestations are the decline of cognitive and memory abilities,aphasia and behavioral changes that gradually deepen with the aggravation of the disease.The pathological features of AD are senile plaques and neurofibrillary tangles.At present,the etiology of AD is not yet clear,its pathogenesis is very complicated,its treatment is quite tricky,and there are few first-line treatments.Chinese medicine has a long history of treating Alzheimer's disease.It has accumulated rich experience in clinical medicine and has the advantages of multiple stages and multiple targets.In this thesis,a combination of traditional Chinese medicine molecular chemistry research strategy,using ligustrazine as the starting material,design and synthesis of 30 ligustrazine esters and ligustrazine chalcone derivatives.Through the evaluation of cholinesterase activity,in order to obtain compounds with significant cholinesterase inhibitory activity,the glutamate-induced SH-SY5 Y cell damage model was used to investigate the neuroprotective effect of the active compounds.Through molecular simulation docking,explain the mechanism of action of active compounds to inhibit cholinesterase.The full text is divided into the following three parts,the author's main contributions are as follows:1.A systematic review of the current status of Alzheimer's disease including the symptoms,pathogenesis,clinical medication,and clinical trials of drugs in progress at the current stage.Explain the important role of combined Chinese medicine molecular chemistry research strategies in drug molecule design.2.Based on the research strategy of combined traditional Chinese medicine molecular chemistry,taking traditional Chinese medicine Chuanxiong Chuanxiong,the active ingredient of Chuanxiong as the starting point,to introduce rhododendron aglycone with nootropic effect into its structure to design and synthesize ligustrazine Ester compounds A1-A20;or introducing chalcone structural fragments with obvious cholinesterase inhibitory activity to design and synthesize ligustrazine chalcone compounds A21-A30.All compounds were characterized by NMR and mass spectrometry,and their structures were correct.3.Using the improved method to detect the cholinesterase inhibitory activity of the compounds,the results show that most of the compounds have good activity.Among them,compound A12,A24,A27 and compound A29 had better inhibitory activity on acetylcholinesterase than positive drug Galantamine,and compound A2,A26,A27 and A28 had better activity on butyrylcholinesterase than positive drug Galant He is sensitive.The neuroprotective effects of active compounds A12 and A27 were evaluated using a glutamate-induced nerve injury model in SH-SY5 Y cells.The results show that compounds A12 and A27 can significantly reduce the cytotoxicity of glutamic acid at different concentrations,improve the survival rate of cells,and have significant differences compared with the model group.This indicates that compounds A12 and A27 have obvious protective effects on glutamate-induced SH-SY5 Y cell damage,which deserves further study.Using Discovery Studio 2019 software for molecular simulation and docking of the compound,the results show that the compound has hydrogen bonding and van der Waals interactions with multiple amino residues.