| Alzheimer’s Disease（AD）,also known as senile dementia,is one of the diseases that the elderly population is prone to.Patients with Alzheimer’s disease usually have obvious cognitive impairment,significant decline in memory,changeable personality irritability,and even affect their language ability,affecting their mental state,causing great adverse impact on their social life,and serious risk of death[1].AD was discovered in the early 20th century and has been documented in detail.It has been playing an important role in scientific research in the medical field for a hundred years,but its complex pathological mechanism has not been fully revealed.In the past few decades,therapeutic strategies for Alzheimer’s disease have focused on improving cholinergic neurotransmission in the brain,which is mainly based on the"cholinergic hypothesis"[2].The cholinergic hypothesis suggests that the memory and cognitive decline of AD is caused by the decrease of choline levels in specific brain regions,and that the inhibition of Cholinesterase（ChE）can effectively improve choline levels and relieve AD symptoms.Its role in the treatment of Alzheimer’s disease has received increasing attention[3].Monoamine oxidase can catalyze oxidative deamination,resulting in the loss of physiological activity of monoamine.AD is a complex disease with multiple pathogenesis and heterogeneity,and simply regulating one pathological mechanism cannot prevent the pathological process well.Different from single-target drugs,multi-target drugs have more advantages in the treatment of diseases,not only the adverse reactions are greatly reduced,but also the use of dosage can be reduced,and the effect is faster.This offers considerable novel ideas for developing treatments for Alzheimer’s and other degenerative neurological diseases.In this paper,we briefly discuss the background of AD,the mechanism of action and the development status of anti-AD drugs.In this paper,a total of 27 tachlin-proparynamine derivatives were designed and synthesized,and all of the structures were detection by high resolution mass spectrometry and nuclear magnetic resonance,and the purity test results were high.The inhibition of cholinesterase inhibition and monoamine oxidase activity of these compounds were determined by Ellman method and Amplex Red fluorescence method,and the blood-brain barrier permeability of these compounds was determined by PMAPA-BBB method,so as to select the best compounds 9d.In addition,acute toxicity studies showed that compound 9d did not cause acute toxicity damage in mice within the range of 2500mg/kg,and pathological studies showed no significant tissue damage in mice.Finally,the effect of compound9d on memory impairment in mice was studied by skip experiment.The results showed that compound 9d could reverse the memory impairment in AD mice,which was consistent with the expected results.In conclusion,the synthesis of molecular compounds that can act on dual targets in this paper provides a considerable basis for the research and development of drugs for the treatment of AD. |
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