Design And Structure-activity Relationships Of Compounds For Adult Hippocampal Neurogenesis

Alzheimer's disease(AD)is a progressive neurological degenerative disorder characterized by occult onset.Alzheimer's disease is the most common type of dementia among the many neurodegenerative diseases,and it is the fourth leading cause of death in people over 65 years of age worl dwide.At present,the pathogenesis of Alzheimer's disease is not clear.The existing therapeutic drugs includ acetylcholinesterase inhibitors(tacrine,donepezil,rivastigmine,etc.)and N-methyl-D-aspartate(NMDA)as receptor antagonist(memantine)can only alleviate the disease and can not prevent and reverse the course of the disease.Neurodegeneration provides a new basis for the treatment of neurodegenerative diseases.However,the existing neurogenic drugs have many problems,such as complicated structure,unstable,easily oxidized,difficult preparation and activity to be tested.In this study,we designed and synthesized different framework scaffolds from the point of neurogenesis,and observed the effect of the compounds on the proliferation and differentiation of neural progenitor cells in hippocampus by immunohistochemical staining.Analysing the relationship between structure and activity,we get drugs with clear scaffold and pharmacophore,which could promote the proliferation and differentiatio n of neural progenitor cells.In the previous work,we designed and synthesized compounds with different skeletons of stilbene,diphenyl ethane,diphenylacetylene and chalcone,and tested their effects on adult neurogenesis.From the relationship between s tructure and activity,we found the most active amide-substituted stilbene(E-4-acylamino-3',4'-methylenedioxy-diphenylethylene).In the present study,we first studied the effect of substituents such as carbonyl,sulfonyl,and thiourea on the activity of stilbene,at the same time,we found a new structure skeleton that can promote the neurogenesis.The following structure-activity relationships were obtained: 1)the activity of the sulfonyl was better than that of the carbonyl;2)the side chain of amide substituent activity: cycloalkane > aromatic > aliphatic chain hydrocarbon;3)the activity of the compound increases as the heteroatom is added to the amide side chain;4)the diphenylpropene compounds obtained by modifying the stilbene skeleton have the activity of promoting neurogenesis,and the activity is slightly higher than that of stilbene.