Synthesis Of 3-Amino-β-Carboline Derivatives And Their Inhibitory Activity On AChE And BuChE

Alzheimer’s disease(AD)is a multifactorial neurodegenerative disorder,characterised by cognitive impairment,which is associated by means of cholinergic hypothesis,to the loss cholinergic of neurons and a decrease in levels of cholinergic neurotransmission.Currently,there is no efficient treatment.Since the introduction of the Amaryllidaceae alkaloid galanthamine as an antidementia drug in 2001,alkaloids have been one of the most attractive groups for searching for new AD drugs.β-carboline,a class of alkaloids with rich structure and a wide range of activity,has been reported in recent years to have good biological activity against acetylcholinesterase(AChE)and butyrylcholinesterase(BuChE),which play an important role in AD.In this study,based on the previous work of the group in the synthesis of β-carboline and its activity,we introduced aromatic groups such as indole at the C-1 position of the parent nucleus structure of β-carboline,linked a series of aliphatic and aromatic amines through amide bonds at the C-3 position,and then conducted inhibition activity experiments on AChE and BuChE in vitro to screen out the active β carbolines,and summarized their structureactivity relationship.After that,the mechanism of action was initially investigated by computer-aided simulation.Theoretical support was provided for the study of β-carboline compounds as anti-Alzheimer’s disease drug.The relevant results are as follows:1.30 3-amino-β-carboline derivatives,all of which are new and unreported,were synthesized by the Pictet-Spengler reaction to construct aromatic substituted β-carboline parent nuclei at the C-1 position,followed by IBX oxidative dehydrogenation,ester hydrolysis and amide condensation steps,and were subjected to 1H NMR,13 C NMR for structural confirmation.2.Tacrine as positive control,the inhibitory activities of 30 compounds against AChE and BuChE were tested by Ellman colorimetric assay in vitro.The results indicate that all compounds showed different degrees of inhibitory activities against the tested enzymes at 8 μM concentration,among which compounds S1 and S12 showed more than 80% inhibition against BuChE with IC50 of 1824.33±188.65 n M,232.86±12.68 n M,respectively.3.Comparison of structural features of the synthesized derivatives with BuChE inhibitory activity show that the introduction of indole substituent at the C-1 position of β-carboline compounds can promote the inhibitory activity of the compounds,and when C-1 is indole,the shorter the fatty amide chain at the C-3 position,the better the activity is,and in the case of aromatic amides,no substitution is preferred to electron-donating substitution,and electron-donating substitution is preferred to electron-withdrawing substitution.4.The molecular docking of two highly active molecules S1 and S12 with BuChE by Auto Dock Vina showed that S1 and S12 may act as an inhibitor of butyrylcholinesterase hydrolysis by competitively binding butyrylcholinesterase.The binding energies of S1 and S12 to butyrylcholinesterase(-11.0 and 11.5 kcal/mol)were much higher than those of butyrylcholine to butyrylcholinesterase(-4.8 kcal/mol),while S1,S12 and butyrylcholine at the key action sites HIS438(residues of the catalytic triad),TRP82(residues of the catalytic anion site)all have strong interactions.In addition,S1 and S12 have more desirable physicochemical parameters.In conclusion,30 β-carboline compounds with AChE and BuChE inhibitory activities were chemically synthesized in this paper,enriching the structural diversity of 3-amino-β-carboline.Molecular docking suggests that the highly active β-carboline compounds may exert BuChE inhibitory activity by competitively binding to butyrylcholinesterase.The results may provide candidate molecules for the development of BuChE inhibitors and may provide some reference for the design and synthesis of β-carboline in cholinesterase inhibitory activity.