Design,Synthesis And Biological Evaluation Of Multitarget Agents Against Alzheimer’s Disease

Alzheimer’s disease(AD),the most common form of dementia,is a chronic neurodegenerative disorder,which is clinically characterized by impairment in memory,complex cognition,language,emotion,and behavior.Several factors,such as levels of acetylcholine(ACh)and amyloid-b-peptide(A?)deposits,play a significant role in the occurrence of AD.Although the pathogenesis of AD is not fully understood,currently the most efficacious treatment approach for AD is considered to increase cholinergic neurotransmission in the brain by lowering Ach hydrolysis.In addition,the protection of nerve cells from Aβ-induced cell damage and apoptosis has a positive effect for the prevention and treatment of AD.Compared with single-targeted drugs,multi-targeted drugs can play a key role in different physiological aspects of the disease,such as less adverse reactions,clinical use of low dose,significant effect and so on.In this study,the 1,2,3-triazole compound MX-1 with novel structural skeleton and good acetylcholinesterase inhibitory activity was used as the lead compound,and then a number of derivatives were synthesized based on the structural modification of MX-1.A related activity test on these synthetic target compound was performed to obtain a potential anti-AD compound 39.This compound exhibited the strongest inhibitory effect on AChE with an IC50 value of 7.23 ?M and a weak inhibitory effect on the Keap1-Nrf2 protein-protein interaction.And it also showed neuroprotective effect against A?25-35-induced neurotoxicity in SH-SY5 Y cells,with 96.5% of cell viability at the concentration of 10μM.In addition,the selected compounds didn’t show obvious cytotoxicity against normal cell lines such as human keratinocytes HaCaT and murine fibroblasts NIH-3T3.Molecular docking indicated that compound 39 had a good affinity with the AChE active site.The calculated results indicated that these synthetic molecules should have suitable BBB penetrability.In conclusion,this study can provide a new molecular model for the design of new highly efficient and safe multi-targeted anti-AD drugs,which is of great significance to develop effective anti-AD drugs and deserves further study.