Study On Design, Synthesis And Biological Activity Of Acetylcholinestase Inhibitors Of Phenylcarbamate Kind

Phenserine,a typical AChE inhibitor of phenylcarbamate kind,is being focused as a great bomb to destroy Alzheimer's Disease.Its dual healing effects on AD,which inhibit APP translation as well as ACHE,will basically change the strategy to cure the disease.Through the methodology of classical drug design,our group designed three series of compounds,including tetrahydroisoquinolin carbamates(Series A and B) and tetrahydronaphthalene carbamates(Series C),which with simple structure and fixed conformation.Based on previously established CATALYST HYPOTHESIS of phenylcarbamates and GOLD fitness scroe,and then screened through ADME property parameters,we selected those compounds with fair drug-likeness score from the previously designed compounds of the three series.Through three kinds ofcyclization,Pictet-Spengler Reaction,PPA-catalyzed cyclization and Bischler-Napieralski Reaction,four kinds of isoquinolins were obtained,which are 6-methoxyl-1,2,3,4-tetrahydroisoquinolin(2),6-methoxyl-1-methyl-3,4-dihydroisoquinolin(13),7-methoxyl-1,2,3,4-tetrahydroisoquinolin(29), 7-methoxyl-1-methyl-3,4-dihydroisoquinolin(35).Affected by different electron distribution of methoxylbenzene,derivatives of 6-methoxylisoquinolin got a better yield than those of 7-methoxylisoquinolin.Nevertheless,1-ethylisoquinolins could hardily conduct a cyclization,as the ethyl substitution is too big to react.And finally we synthesized those compounds through methylating theβsite of protonized imine.The result shows that AChE inhibition activities of all the hydroxylisoquinolins are rather poor,but their dimethylcarbamate derivates and phenylcarbamate derivates could inhibit AChE strongly.Especially,he mean inhibiting percent of QQ602,QQ605,QQ609,QQ618 and QQ621 exceeded 50%. Among the compounds of Series A and B,alkylating 1 site of phenylcarbamates could raise the ability of inhibiting AChE further.When its concentration is 1^* 10^-7mol/L, QQ609 could inhibit 79.8%of AChE,that tops the others.Even its concentration diluting 10 times,1^*10^-8mol/L,it still could inhibit 33.2%of AChE.The inhibiting ability of QQ609 is stronger than the comparison,Huperzine A,and the well-selling drug Rivastigmine.QQ609 also shows the best estimated IC₅₀ value according to CATALYST HYPOTHESIS,which matches the biological activity.Then,we could deduce that the CATALYST HYPOTHESIS could be applied in those phenylcarbamates of Series A and B.QQ609 is a promising compound.For further study on QQ609,the important intermediate of QQ-609,QQ607,was salified with L-DBTA in ethanol,and R-QQ607·L-DBTA was recrystallize from the solution,which was confirmed by single X-ray diffraction.We have synthesized 43 compounds totally,including 20 target compounds, and 16 among them are novel ones.