Design,synthesis And Biological Evaluation Of Tacrine-n-butylphthalide Hybrids As Multifunctional Cholinesterase Inhibitors

Alzheimer's disease?AD?is a complex chronic progressive neurodegenerative disorder,and it seriously causes the dementia in elderly people and aflicts millions of people worldwide.It has been demonstrated that loss of cholinergic transmission is one of the most significant causes for AD,and cholinesterase inhibitors is still the most important anti-AD drug.Given the complicated etiology and pathological mechanism of AD,existing drugs can only reverse the symptoms in a short period instead of halting or curing the neurodegeneration,which fail to fulfill the needs of clinical treatment.At present,the treatment of AD with multitargets has become the research focus,and the design and synthesis of acetylcholinesterase inhibitor based on multi-target anti AD drug is most important research directions.In this paper,with genipin as starting material,21 tacrine-n-butylphthalide hybrids were designed,synthesized by using cholinesterase?ChE?inhibitors tacrine as the basis,and they were confirmed by IR,¹H NMR,¹³C NMR and ESI-MS.Subsequently,cholinesterase inhibitory activitiy,neuronal cells antioxidant activity and structure-activity relationships were studied in vitro.The preliminary pharmacological results indicated that all of these compounds had inhibitory activity on both cholinesterases?AChE and BuChE?.Compounds 10b,14a,17d and 17g exhibited more significant AChE inhibitory activities than positive reference tacrine,and 10g showed more significant BuChE inhibitory activities than positive references donepezil and similar to to tacrine.The ROS levels effects of compounds 10b,10g,14a,17d and 17g were further studied by A?_1-42-induced neurotoxicity in rat hippocampal neurons.The efficacy results showed that these compounds had potent inhibitory activity for rat hippocampal neuronal cells secreting ROS induced by A?_1-42.Moreover,molecular docking simulation were carried out to study the binding mode compound 10b in AChE.The work in this paper has certain value for the development for anti-AD drug.