Synthesis And Cholinesterase Inhibitory Activity Of 4-N-phenylaminoquinoline Derivatives Containing N-methylbenzylamine Groups

The diagnosis and treatment of Alzheimer's disease?AD?is one of the most urgent research hotspot in the world.Cognitive decline is often associated with extracellular senile plaques,increased levels of intracellular neurofibrillary tangles?NFT?,and gradual closure of cholinergic basal forebrain neuronal transmission.Among them,two types of lesions have been mainly discovered and extensively studied:amyloid plaques and neurofibrillary tangles?NFT?.These two dysfunctional lesions are caused by the aggregation of two proteins,amyloid beta peptide and tau protein,respectively.Even in the course of the treatment of AD,there are several important research directions,but so far the only approved medicine is still the use of cholinesterase inhibitors.Furthermore,it has been confirmed that acetylcholinesterase?AChE?and butyrylcholinesterase?BuChE?enzymes are not only responsible for acetylcholine levels,but also play a key role in A?-aggregation in the early stages of senile plaque formation.In such a complex and broad framework,heterocyclic molecules are essential backbones for the construction of new,selective drugs and diagnostic probes.Based on this,a series of 4-N-phenylaminoquinoline derivatives containing N-methylbenzylamine groups were synthesized by systematic investigation.The pure compounds were obtained by column chromatography purification,and the structural characterization of the compounds was confirmed by HR-ESI-MS?¹H-NMR?¹³C-NMR and IR.The inhibitory activities of AChE and BChE of this series of compounds were then determined by the Ellman method.Through data analysis,whether for AChE or BChE,the compound with a nitro group attached to the 3-position of the quinoline ring of the target compound is more active than the compound with an amino group,which indicates that the 4-N-substituted aniline ring and the quinoline ring are present.When the electron withdrawing group is attached to the 3 position,the AChE inhibitory activity is enhanced;when the electron donating group is attached,the inhibitory activity is lowered.All of the target compounds 10A to 10N containing a nitro group had good AChE inhibitory activities.Compound 10D?2.65±0.52?M?inhibited the activity of BChE,which was 9 times stronger than the galantamine reference drug?24.41±2.01?M?.Molecular docking simulation studies of the target compounds were carried out using Discovery Studio 4.5 software,which partly clarified the difference in activity inhibition caused by the different structural structures of the compounds.The LogP value of the target compound was simulated by Chemdraw to judge the lipophilic strength of the target compound,which provided a theoretical basis for judging whether the drug easily penetrated the blood-brain barrier.