Design,Synthesis And Anti-Alzheimer’s Disease Activities Of Novel S-Triazine Derivatives

In this study,two series of triazine derivatives were designed and synthesized using benzimidazole and 1,3,5-triazine as raw materials,and the biological activities of these compounds were verified by various experiments.These findings provide data and theoretical support for future studies on triazine-benzimidazole derivatives.In this experiment,1,3,5-trichlorotriazine was used as the raw material,and 12 different monosubstituted triazine intermediates were obtained by dropwise addition of different secondary amines at-10°C.The structure was confirmed by ¹H-NMR spectroscopy,dry and reserve.Then the intermediate of benzimidazole-piperazine and the intermediate of methyl benzimidazole-piperazine were synthesized at 120°C and 86°C,respectively.Finally,24 triazine-benzimidazole derivatives were synthesized at room temperature.In addition to their structural confirmation by NMR and high resolution mass spectrometry（HRMS）,two single crystal compounds 6c,6j were also grown,and their structures were resolved by X-ray single crystal diffraction.The inhibitory activity of 24 compounds on acetylcholinesterase and butyrylcholinesterase was screened by Ellman method,and 18 selective acetylcholinesterase inhibitors were screened through screening,and the inhibitory concentration reachedμM level.Among them,compound 9f has the best inhibitory activity on acetylcholinesterase,and its IC₅₀ result is 0.044±0.002μM,and the IC₅₀ result of the Donepezil is 0.052±0.004μM.It indicated that the inhibitory effect of 9f on acetylcholinesterase would be better,and the inhibitory effect of 9f on acetylcholinesterase was dose-dependent.Compound 9f was selected as the verification.Through the molecular docking simulation study between compound 9f and acetylcholinesterase,it was found that compound 9f binds to the CAS site and PAS site of acetylcholinesterase through H bond,P-cation interaction,π-πinteraction and hydrophobic interaction.Thereby inhibiting the activity of acetylcholinesterase.The correctness and reliability of the results of the molecular docking experiments were verified by kinetic simulation experiments.From the results of chelation experiments between 9f and metal ion solutions,it can be known that 9f easily chelates with metal ions in metal solutions.Therefore,9f is expected to be used to improve the condition of AD patients by regulating the metal ions level in the brain of AD patients.According to ADME prediction,it is found that most of the compounds synthesized that most of them can pass through the blood-brain barrier,and none of them have chemical teratogenic effects.The target compounds obtained in this study were all confirmed by nuclear magnetic resonance ¹H-NMR,¹³C-NMR,FTIR,HRMS and X-ray single crystal diffraction（XRD）.And the above experimental results,the compounds synthesized in this study are expected to be used as lead compounds for anti-Alzheimer’s disease to be further studied.This paper contains 57 pictures,9 tables and 110 references.