Synthesis And Cholinesterase Activity Evaluation Of Flavonoids Derivative Based On B-ring Transform

Flavonoids is a class of natural products widely distributed in plants,And their core structure is benzo chromone.According to IUPAC nomenclature,three rings in the flavonoid structure are called A-ring,B-ring and C-ring.Many research shows that flavonoids have many biological activities such as anti-oxidation,anti-tumor,anti-inflammatory,anti-viral and so on.In the previous work,our research gruop using skeleton migration strategy to synthesize flavonoids from chalcone,and a series of flavonoid derivatives with cholinesterase activity were discovered.Based on the previous work,this subject is extended as follows:Firstly,effects of changing the B-ring aromatic system on biological activity are explored.At the same time,the previous research ideas were continued,and the different tertiary amine groups were also in consideration.Secondly,the compound 3a₁ having a good inhibitory effect on AChE was selected as the main research object,3a₁ permeable brain barrier of the different sex mice was preliminarily studied.Research content and results:（1）By increasing a fused ring aromatic system of B-ring,Design and synthesized the compounds containing tertiary amine side chain that 2-phenyl-chromone derivatives,2-naphthyl-chromone derivatives,2-anthryl-chromone derivatives.And Determine the inhibitory effect of compounds on cholinesterase exploring the relevant structure-activity relationship The results showed that compounds 3a₁ and 3b₁exhibited higher inhibitory activities on AChE with IC₅₀=1.29±0.10μmol/L and0.80±0.04μmol/L,respectively.The fused form increases the flavonoid B ring aromatic system,and the inhibitory activity of the compound on AChE is significantly decreased.The inhibition of cholinesterase by different nitrogen-containing compounds is pyrrolidine>piperidine>dimethylamino;The inhibition of AChE activity in different positions was 6-positions>7-positions>5-positions,and the inhibition activity of BuChE was 5-positions>7-positions>6-positions.（2）Based on the study of fused ring aromatic system,the flavonoid B ring was replaced by a non-aromatic cyclohexane ring and a non-fused biphenyl ring,also different tertiary amine side chains were introduced at the 6-position of the A ring.The results of Cholinesterase inhibitory assay showed that when the B ring does not have aromaticity,the compound still has cholinesterase inhibition,but the inhibition is weaker than before;when the B ring is a non-fused aromatic biphenyl ring,the compound inhibitory effect on cholinesterase is enhanced,and the IC₅₀0 of AChE is up to 0.65±0.03μmol/L（3k₁）.Compared with the 2-naphthyl chromone derivative of the fused ring aromatic system,this series of compounds are choline esters,the inhibition of the enzyme is better.（3）A compound with strong inhibitory effect on cholinesterase was selected for molecular docking experiments in every aromatic system.Molecular docking experiments have shown that the binding of compounds to cholinesterase occurs mainly in two catalytically active catalytic centers（CAS）and active catalytic centers（PAS）.The binding occurred in the CAS region is related to the protonated nitrogen atom,and the binding occurring in the PAS region is dominated by H-πinteraction andπ-πstacking.When fused to increase the B-ring aromatic system,the binding sites of the compound in the PAS region increase,but the binding sites in the CAS region are less;when the B-ring is a non-fused form of the biphenyl ring,the compound is in the PAS region and The binding sites in the CAS region are simultaneously increased（4）Compound 3a₁ was selected as the research object,and the permeability of3a₁ to the blood-brain barrier of mice was preliminarily studied.The mice with different genders were divided into 7 groups,one group was blank control group,and the other 6 groups were experimental group.Experimental group administered by intragastric,The blood and brain tissues of the mice were removed after administration.at 0.25 h,0.5 h,1 h,2 h,6 h,15 h,respectively.The content of 3a₁ in brain samples and serum samples was determined by high performance liquid chromatography.The preliminary results showed that compound 3a₁ could through the blood-brain barrier of mice,and 3a₁ had better permeability to the blood-brain barrier of female mice.After administration 0.5 h,3a₁ was detected in brain and serum.At 1 h after administration,3a₁ reached the peak content of brain tissue.After 15 h of administration,the compound was completely eliminated in mouse brain and serum.