Synthesis And Biological Activity Of Quinoline Derivatives Containing Small-molecule Tertiary Amine Moieties

Alzheimer’s disease（AD）is an irreversible progressive neurodegenerative disease characterized by memory loss,impaired thinking and reasoning,and personality and behavioral changes.Due to the diverse and complex causes of Alzheimer’s disease,drug research for Alzheimer’s disease has been difficult.In order to solve this problem and find multi-target drugs for Alzheimer’s disease,our group has been researching for many years.Quinoline derivatives containing tertiary amine groups were found to have good cholinesterase inhibitory ability.Based on 4-N-phenylaminoquinoline as the parent ring,a series of compounds were synthesized by modifying and transforming them by introducing different tertiary amine groups and by modifying different carbon chain lengths.The acetylcholinesterase and butyrylcholinesterase inhibitory activities of this series of compounds were then determined by the Ellman method.The compounds were also evaluated for their DPPH radical scavenging activity,ABTS radical scavenging activity,and predicted their drug-forming properties.After the activity test results,it was observed that all the compounds had some cholinesterase inhibitory ability and most of them had good antioxidant capacity.Among them,compounds 10J(IC₅₀=2.48μM),10K(IC₅₀=1.17μM),10N(IC₅₀=3.82μM),10O(IC₅₀=1.71μM)had good ACh E inhibitory ability,while compounds10O(IC₅₀=43.76μM),10K(IC₅₀=21.11μM)had good BCh E inhibitory ability.Compounds 10C(IC₅₀=11.55μM)and 10O(IC₅₀=3.46μM)showed good DPPH radical clearing ability,and compounds 10B(IC₅₀=23.33μM)and 10K(IC₅₀=9.51μM)showed good ABTS radical clearing ability.The BBB simulations showed that most of the compounds satisfied the Lipinksi principle.Through this series of pharmacological activity tests and evaluations,quinoline derivatives containing piperidine moieties showed better cholinesterase inhibition,and among them,the shorter the carbon chain length,the stronger the cholinesterase inhibition ability of the compounds.Also,compounds containing electron-donating groups on 4-N phenylamino groups would have better DPPH radical scavenging ability and ABTS radical scavenging ability.This series of results shows that quinoline derivatives containing substituted tertiary amine groups are of scientific value for in-depth study and provide new ideas and directions for the study of AD drugs.