Design,Synthesis And Activity Evaluation Of Multi-Target Anti-Alzheimer's Drug Leads Based On Natural Product Pharmacophores

Alzheimer's disease?AD?has become the third leading cause of death after cancer and cardiovascular diseases.The pathogenesis of Alzheimer's disease is complex,so far,only 7drugs have been put on the market for clinical relief of Alzheimer's disease,and they have not been able to provide effective treatment.Most of the drugs have obvious drug resistance and side effects?such as liver toxicity,nausea,vomiting and heart failure,etc.?.Therefore,in the face of the large population of Alzheimer's disease in the world,it is urgent to develop an anti-AD drug with high efficiency and low toxicity.It is well known that marine natural products not only have rich structural diversity,but also have unique Biological activity.The marine-derived natural product Pulmonarin B not only has moderate cholinesterase inhibitory activity(AChE:IC₅₀=37.02±2.11?M;BChE:IC₅₀=30.70±1.44?M),but also has obvious resistance tob-amyloid aggregation ability?self-induction model:29.78±1.45%,AChE induction model:27.60±1.96%?;while the Phidianidine B derivatives have been reported to have protective effects on human neuroblastoma cells induced by oxidative free radicals such as Ab,H₂O₂,and oxygen-sugar deficiency.Therefore,based on the anti-Alzheimer's cholinergic hypothesis and amyloid hypothesis,structural design,modification and optimization of structural derivatives derived from marine novel bromobenzene compound Pulmonarin B?1?and indole compound Phidianidine B?2?and carried out a variety of anti-AD related activity tests and cytotoxicity tests in this paper.In this paper,a total of 20 new bromophenylacetic acid derivatives?13a-13h,14a-14l?and 23 Indole derivatives?15a-15p,16a-16g?,and tested in vitro enzyme activity and enzyme kinetics.Preliminary experimental results show that the above two types of compounds show good inhibitory activity of dualcholinesterase,especially compound 14j has the most significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase(AChE:IC₅₀=0.182±0.006?M;BChE:IC₅₀=0.064±0.006?M),compound 16e(AChE:IC₅₀=0.173±0.012?M;BChE:IC₅₀=0.066±0.003?M).In addition,compound 16e?50 nM?can significantly increase the frequency of nerve electrical activity and reduce the duration of each burst of nerve electrical activity.Compound 14j also showed significant anti-amyloid aggregation activity?self-induced:32.37±0.62%;acetylcholinesterase induced:47.73±4.35%?.In vitro cytotoxic biological experiments on HepG2 cells showed that compound 14j has extremely low cytotoxicity(IC₅₀>80?M).The research on this subject shows that the bromophenylacetic acid-tacrine structural fragment based on the natural product Pulmomarin B has good cholinesterase inhibitory activity and anti-amyloid aggregation activity,and some compounds also show extremely low cytotoxicity in the highly active range.The indole derivatives based on the marine natural product Phidianidine B also have good dual-cholinesterase inhibitory activity and good nerve electrical activity improvement.Therefore,the two types of compounds can be used as multi-target anti-AD hit-compounds,and their subsequent deeper structural optimization and activity modification will provide potential candidate compounds for anti-AD drug development.