Palladium-catalyzed Synthesis Of Aryl Huperzine A Derivatives And Their Anti-AD Activity

Huperzine A is a natural sesquiterpene alkaloid obtained from Huperzia serrata.It is an efficient and highly selective reversible acetylcholinesterase inhibitor.It is mainly used to treat Alzheimer’s disease(AD),but it also has many side effects(such as dizziness,nausea,vomiting,diarrhea,fatigue and loss of appetite,etc).Therefore,new huperzine A derivatives with relatively good synthesis activity and relatively low toxic and side effects are used for anti-AD activity screening,which is of great significance in the discovery of new-generation anti-AD drugs.Based on the structure-activity relationship of huperzine A,this project adopts the Late-stage C-H/N-H functionalization strategy,and applies the metal-catalyzed method to the chemical structure modification of natural product huperzine A.Palladium-catalyzed Suzuki-Miyaura and Buchwald-Hartwig coupling reactions can introduce phenyl and aromatic heterocycles with diverse structures and different substituents into huperzine A.The pyridone carbonyl and primary amino group of huperzine A were modified.Two series of huperzine A derivatives,namely decarbonylaryl huperzine A derivatives and N-aryl huperzine A derivatives,were rapidly and efficiently synthesized.The synthetic compounds were further investigated for their neuroprotective activity.A total of 56 new huperzine A derivatives were synthesized in this project,including 24 decarbonylaryl huperzine A derivatives and 32 new N-aryl huperzine A derivatives,and the structures of the synthesized compounds were identified.In vitro anti-ACh E activity of 24 decarbonylaryl huperzine A derivatives was tested.In vitro anti-ACh E/Bu Ch E activity test,in vitro neuroprotective activity test of SH-SY5 Y cells,molecular docking test and blood-brain barrier permeability prediction were carried out on 32 synthesized new N-aryl huperzine A derivatives.The structure-activity relationship of synthesized compounds anti-ACh E activity was summarized.The results showed that the N-aryl derivatives had strong anti-ACh E activity.Among them,the anti-ACh E activity of pyridine derivative N-(5-methoxypyridine-2-yl)-huperzine A(30)was significantly improved.However,the decarbonylaryl huperzine A derivatives did not show stronger anti-ACh E activity.This indicats that the pyridone carbonyl group is an essential pharmacophore for the anti-ACh E activity of huperzine A,which further enhances the understanding of the structure-activity relationship of huperzine A aganist AChE.