Synthesis And Cholinesterase Inhibition Activity Of Chalcone Derivatives Which Contains Nitrogen As Twin Drug

Chalcone is a class of natural flavonoid compounds that exist in a variety of plants and has many important biological activities.In recent years,many researchers have focused on this type of compound,made a lot of important progress.In the past few years,our laboratory continually worked on the structure activity relationships of chalcone derivatives,such as:We simplified the structure of flavokawain B to design and synthesis a series of 3'-(tertiary amines)alkoxychalcone derivatives.We synthesized a series of 4'-(tertiary amines)alkoxychalcone derivatives and halogenated chalcone derivatives based on chalcone skeleton,then we studied their the structure-activity relationships.On previous research,according to AChE double active sites hypothesis and twin drug design principle,we synthesized a series of chalcone derivatives with different lengths of methylene side chains at different position and different tertiary amines groups.We carried out the preliminary structure activity relationships study against AChE and BuChE.This paper mainly carried out the following work:1,A series of 4,4'-di(tertiary amines)alkoxychalcone derivatives with different lengths of methylene chain were synthesized.The results of structure activity relationships showed that the synthesized compounds had different effects on acetylcholinesterase.However,the 4,4'-dihydroxychalcone as a lead compound did not have a corresponding acetylcholinesterase inhibitory activity.It was confirmed that the terminal tertiary amine substituents of the synthesized compound were used to enhance the AChE inhibitory activity.The subsequent study on the structure-activity relationships shows that the effects of different terminal tertiary amine substituents on the AChE inhibition are:pyrrolidinyl>piperidinyl>dimethylamino.When the terminal substituents are the same,the effect of the increase of the AChE inhibitory activity on the compounds with different length of chains are:The compound with two carbons in methylene side chains have a better bioactivity for AChE than other compounds.Compounds 3a,3b and 3c have the strongest inhibitory activity and the highest selectivity for AChE,the IC50 reached 0.16?0.047 and 0.093 ?mol/L respectively.2,A series of highly active di(tertiary amines)ethyloxychalcone derivatives with two carbon atoms at the side chain and different group position were synthesized.The results of structure activity relationship showed that the meta-compounds had the highest activity in all three positions:ortho(2,4'),meta(3,4')and para(4,4').In three terminal tertiary amine substituents(pyrrolidinyl?piperidinyl?dimethylamino),the pyrrolidinyl is the best one,so that the compound 16b with meta position and pyrrolidinyl get the highest bioactivity,which IC50 is 0.031 ?mol/L,354 fold compared to Rivastigmine.3,To explore the mechanism of inhibition,modulate the AChE and BuChE inhibitory activities of the newly synthetic compounds,We performed molecular docking for some of the highly reactive 4,4'-and all derivatives of 2,4'-and 3,4'-di-tertiary amine alkoxychalcone.The results of the experiments show that compounds with high AChE inhibitory activity can bind to CAS and PAS simultaneously,with four binding sites,but the lower active compounds generally have only two or even fewer binding sites.The results of the above-mentioned molecular docking can partially explain the difference in the inhibitory effect of the compound on cholinesterase.