Synthesis And Cholinesterase Activity Evaluation Of Coumarin-chalcone Hybrid Derivatives

Alzheimer's disease?AD?is a primary degenerative disease of the central nervous system that occurs in the elderly and pre-senile.Although there are multiple theories about its pathogenesis,with the failure of the development of new AD drugs targeting?-amyloidprotein,5HTR6andBACE1inrecentyears,Asaresult,acetylcholinesterase inhibitors?AChEI?drugs are still the first choice for the treatment of AD.Clinical experiments have proved that AChEI is effective in relieving cognitive impairment in patients with AD.Therefore,the development of AChEI with high activity,high selectivity,and low side effects is still one of the goals for the development of anti-AD drugs.In the previous study,our research group found that the nitrogen derivatives of Flavokawain B which containing chalcones had good inhibitory activity against acetylcholinesterase?AChE?.On this basis,structural simplification and modification of Flavokawain B,a series of chalcone,ferulic acid and cinnamic acid containing nitrogen derivatives widely existed in natural products were designed and synthesized.The results of activity determination showed that the series of compounds were very strong AChEI.Hence,searching for AChEI from natural products is one of the effective methods.Coumarins are ubiquitous natural products in nature and have a wide range of biological activities.We use the Combination principles to combine the nucleus structure of coumarin and chalcone in one molecule.This hybrid molecule can combine with the two sites of the active site and the peripheral anionic site of AChE to improve the inhibitory activity to AChE.?1?A series of coumarone heterozygous derivatives containing tertiary amine side chain or alkyl side chain with different substitutions were designed and synthesized.The effects of the type of side chain and the substitution position on the inhibition of AChE activity were studied.Furthermore,the carbonyl group was introduced to the adjacent carbon atoms adjacent to the side chain of tertiary amine,and the derivatives of the amide side chain were formed in the structure.The effect of the introduction of space steric resistance on the biological activity of the compound was preliminarily explored.After the activity assay,the best derivatives were screened for ring closing reaction to study the relationship between cyclization products and biological activities.The data showed that the derivatives of the side chain containing tertiary amine were all larger than the derivatives of the alkyl side chain,which proved that the side chain of tertiary amine had a vital role in the biological activity of such compounds.When the tertiary amine side chain is the same,the overall change in the biological activity of the compound is:4'-substituent>3'-substituent>2'-substituent,and the change rule forthebiologicalactivityofinhibitingBuChEis:3'-Substituent>2'-Substituent>4'-Substituent.When the side chains are the same,the substituent type has a clear rule for the AChE inhibitory activity of the compound:tetrahydropyrrolyl>dimethylamino>piperidyl>diethylamino>morpholinyl>isopropyl>i sobutenyl.The compound with the best AChE inhibitory activity was D_5e(IC₅₀=0.15±0.01?mol/L,selectivity is 27.40);and after the methoxy group was introduced into the tertiary amine side chain with the exception of compound D_12m(IC₅₀=0.37±0.02?mol/L).With activity enhancement,the activity of other methoxy-incorporating compounds decreased.The result shows that the law is:without methoxy>one methoxy>two methoxy,the change of inhibitory activity of BuChE is:introducing an methoxy>without methoxy>introducing two methoxyl groups;after the introduction of carbonyl structure in the tertiary amine presence,the enzyme inhibitory activity of most of the compounds disappears(IC₅₀>500 mol/L).After cyclization in the derivative structure,the activity of the compounds decreased,which proved that the flexible structure of acryl ketone could enhance the inhibitory activity on AChE.Heterocyclic derivatives D_14n4n had the best inhibitory activity on AChE(IC₅₀=0.36±0.02 mol/L).?2?A series of 4-pentadien-3-one derivatives containing different tertiary amine substituentsanddifferent substitution positions were synthesized,andthe structure-activity relationship of the AChE inhibitory effect of coumarin chalcone nitrogen-containing derivatives was further explored.The results showed that the activity of the compounds relative to the coumarin chalcone hybrid derivatives generally decreased.When the tertiary amine side chains are in the same position,the biological activity rule is:tetrahydropyrrolyl>dimethylamino>piperidinyl;when the tertiary amine groups are the same,the effect of substituent position on the activity of the compound is 4'-substitution.>3'-Substitution>2'-Substitution,same as coumarin chalcone hybrid derivatives.Among them,compound E_3ee has the highest inhibitory activity against AChE(IC₅₀=0.76±0.03?mol/L).?3?Using MOE 2014 to conduct molecular docking experiments,explore the three-dimensional combination of compounds and AChE.in order to assist in explaining the impact of structural differences on biological activity.The results of molecular docking experiments were basically in agreement with the results of compound activity assays.