Design,Synthesis And Evaluation Of Dinitrile Isophorone Derivatives As Anti-alzheimer Theranostic Agents

Alzheimer's disease(AD)is a chronic central nervous degeneration disease characterized by progressive memory and cognitive dysfunction.The main symptoms of AD patients are progressive memory disorders,cognitive dysfunction,personality changes and language disorders and so on,and AD seriously affects social,professional and life functions.The pathogenesis of AD is not clear,because it involves the participation of many related factors.At present,the only speculations and assumptions based on limited observations,including cholinergic hypothesis,?-amyloid(A?)cascade hypothesis,Tau protein hyperphosphorylation hypothesis,inflammation and immunology,etc.Among them,the A?-cascade hypothesis is widely accepted.It is believed that in the early stage of AD,due to mutations in its precursor protein genes,etc.,abnormal deposition of A? protein and the formation of A? plaque.These plaques can cause oxidative stress and inflammation,eventually lead to neuron degradation and loss.In view of the fact that A? plaques are the early etiology of AD,research on small molecule compounds that can detect and treat A? plaques is very meaningful for the early detection and treatment of AD.On the basis of literature research,combined with previous research work,the main contents of this paper include:(1)Reviewed the pathological mechanism of AD and research progress of A? plaques.(2)Design and synthesis of anti-AD agents,using dinitrile isophorone as the basic fragment,connecting polyamine-modified aromatic aldehydes and naphtholactam aldehydes to synthesize two series of compounds: the first series includes 18 compounds,13 of which were not reported.They were obtained by usingaromatic aldehyde modified at the 4-position and condensed with dinitrile isophorone.The second series is the modification of naphtholactam aldehyde,which is combined with dinitrile isophorone to obtain 17 target compounds.The structures and purity of all target compounds were confirmed by 1H NMR,13 C NMR,MS and elemental analysis.(3)Evaluation of anti-AD agents.The inhibitory activity of the compounds against cholinesterase was tested by Ellman method.The results showed that the inhibitory activity of the two series of compounds on cholinesterase was better than the control drug Rivastigmine,and most of the compounds showed cholinesterase performance medium inhibitory activity.The Th T fluorescence spectroscopy was used to test the inhibitory activity of the target compound on A? self-aggregation.The results showed that the inhibitory activity was better than that of the control drug curcumin.The toxicity of the target compound on nerve cells was tested by MTT assay.Conclusion,the target compounds synthesized in this paper basically achieved the original design purpose.Among them,the compound 7i and 7m has a longer fluorescence emission wavelength,and its inhibitory activity on A? self-aggregation is better than that of curcumin.They showed less toxic to nerve cells,therefore,they can be considered as near-infrared fluorescent probes to detect A? plaques in AD.