Studies On The Structure-activity Relationship Of Cinnamic Derivatives With Cholinesterase

In recent years,many clinical studies have failed,which target ?-amyloid,5HTR6 and BACE1 as AD's treatment.Based on the research of Acetylcholinesterase,acetylcholinesterase inhibitors(AChEI),which could improve the Alzheimer's disease(AD)in patients with cognitive dysfunction have exact curative effect.The development of the new type of AChEI is still the main way to develop the treatment of AD.Structural transformation of natural products is an important method for developing new drugs.In previous work,as a nature product,flavokawain B has been simplified.The chalcone skeleton was retained to synthesize a series of chalcone derivates containing tertiary amine.Besides,halogenated chalcone derivatives and chalcone analogues containing heterocycles were also synthesized.They have potent inhibitory activity of acetylcholinesterase(AChE).Structure-activity relationship(SAR)studies have shown that the structure of acrylketone and tertiary amino side chains could be necessary groups for chalcone derivatives in inhibition activity of AChE,Moreover,the types and position of substituted tertiary amine side chain can influence the inhibitory activity.In addition,amide linkage is similar with peptide bonds,which exist in proteins in the body and can be degraded under certain condition.It is indicated that the introduction of amide linkage to derivatives would enhance the biocompatibility.According to these opinions,this topic selected the cinnamic acid,which has the structure of acrylketone as the research object,and connected it with the tertiary amine groups.The chalcone was replaced with cinnamamide to get a series of cinnamic acid derivatives.The phenethyl,pentadiene,pentyl and halogenated styryl were substituted with styryl of cinnamamide in order to further study of benzene,double bond and halogen on the effect of cholinesterase inhibition activity.This paper discussed its SAR and selected the highly active novels as AChEI.The main contents of this paper were summarized as following:(1)A series of cinnamic acid derivatives(Aia-A3d),phenylpropionic acid derivatives(B1a-B3d),sorbic acid derivatives(C1a-C3d)and hexanoic acid derivatives(D1a-D3d)containing aminoalkyl group side chains were designed and synthesized to explore the influence on AChE of mother nucleus structure types,tertiary amine types and substituted position.The most potent inhibitory activity of AChE is A3d(IC50=3.64±0.28 ?mol/L),and that of the butyryl cholinesterase(Butyrylcholinesterase,BuChE)is D2c(IC50=0.22±0.02 ?mol/L).The results of SAR research showed that the introduction of the same type of tertiary amine groups at the same position,the enhancement of the AChE inhibitory activity was as follows:sorbic acid derivatives>hexanoic acid derivatives;In addition to the Aia-Dia,Aid-Did and A3b-D3b,cinnamic acid derivatives>sorbic acid derivatives>phenylpropionic acid derivatives;The comparison of phenylpropionic acid derivatives and their corresponding hexanoic acid derivatives in the inhibitory activity was not clear.The para-substituted derivatives showed the higher inhibitory activity of AChE than the ones at other substituted position in general.For the same parent nucleus derivatives,the introduction of different types of tertiary amine groups at the same position showed the different AChE inhibitory activity.For the cinnamic acid derivatives and phenylpropionic acid derivatives,the inhibitory potency of the derivatives against AChE followed the general order:pyrrole>piperidine ?dimethyl amine>diethyl amine;For the sorbic acid derivatives and hexanoic acid derivatives,the derivatives with diethyl amine showed minimum inhibitory activity,while the compounds with pyrrole,piperidine and dimethyl lamine substituted didn't have regularity with inhibitory activity.(2)The design and synthesis of a series of fluorinated cinnamic acid derivatives(E3a-G3 d)and chlorinated cinnamic acid derivatives(H3a-J3d)were substituted for the tertiary amines.To explore the types of tertiary amines,the substituted position and their species of halogen atoms in halon cinnamic acid derivatives on the SAR with cholinesterase.The compound with the highest level of the inhibition of AChE is G3d(IC50=1.1±0.28 ?mol/L),and the highest compound in BuChE is H3d(IC50=13.34±1.02 p?mol/L).The results of SAR showed that the cinnamic acid derivatives containing dimethyl,piperidine or pyrrole group side chains,were substituted with fluorine atoms or chlorine atom,which could strengthen the AChE inhibitory activity.the inhibitory potency of the compounds with different substituted position against AChE followed the order:para-substituted>meta-substituted>ortho-substituted;the cinnamic acid derivatives containing diethyl group side chains were substituted with fluorine atoms or chlorine atom,which could weaken the AChE inhibitory activity.The position and the weakened relationship had no obvious relativity.When halogen atoms were introduced at the same position with the same type,the different aminoalkyl groups of halon cinnamic acid derivatives had different AChE inhibitory activity,the inhibitory potency of the derivatives against AChE followed the general order:pyrrole>dimethyl amine>piperidine>diethyl amine.(3)The enzyme kinetics of AChE were conducted by the compounds(A3d?B3d?C3d?D3d?G3d?J3d),which were screened by the analysis of the enzymes with the high inhibitory activity of AChE.Enzyme kinetics experiments showed that the type of inhibition between compounds and AChE was a mixed type.It was indicated that the compounds could combine with Catalytic activity center(CAS)and the peripheral binding site(PAS).(4)MOE2008 software is used as a molecular docking technique.The combination of the compound with AChE protein was studied.Molecular docking experiments showed that the compound can interact with CAS and PAS.In the region of CAS,the main protons of the compound interacted with cation-? and Trp84.In the region of PAS,cinnamic acid derivatives and phenylpropionic acid derivatives were mainly connected through the ?-? accumulation,which was produced by aromatic ring and the amino acid residues of benzene parallel.Replacing styrene with pentadiene or substituting phenethyl with pentane,the derivatives got more flexible.They could connect with AChE protein via hydrogen bond by rotating to the best conformation into cavity;The same derivatives with the same mother nucleus have the same function with AChE,while the stability and the binding energy of them are different and showed different biological activity.The aromatic ring was substituted with halogen,most compounds can also be interacted with AChE through the hydrogen bonding.These results could explain that the derivatives with different biological activity at the molecular level.