Synthesis,Characterization And Inhibitory Activity Against PTP1B Of Novel Containing Mono-/Bis-carbazole Moiety N-acylhydrazone Derivatives

1.In this paper,fifty-two novel containing Mono-/Bis-carbazole moiety N-acylhydrazone derivatives,twenty arylaminoacetylhydrazone derivatives containing carbazole moiety TM-I-5a～5t,fifteen N-acylhydrazone derivatives containing mono-/bis-carbazole ring TM-II-5a～5o,fifteen N-acylhydrazone derivatives containing carbazole ring and aromatic ring/aromatic fused heterocycle TM-III-6a～6h,TM-III-7a～7f,TM-III-8 and two bisarylaminoacetylhydrazone derivatives containing carbazole ring TM-III-11a～11b,were designed and synthesized on the basis of reviewing a large number of literatures.The structures of the target compounds were characterized by IR,NMR(including¹H NMR,¹³C NMR and 2D NMR),MS and elemental analysis.2.The inhibitory activities of target compounds TM-I～III against PTP1B were evaluated.The experimental results show that:（1）.Among the target compounds TM-I series,all the target compounds TM-I-5a～5t show higher inhibitory activities against PTP1B,IC₅₀=[（2.78±0.04）～（9.91±1.72）]μmol/L.Most compounds have higher activities than the control drug oleanolic acid（OA）.Among them,the compound TM-I-5t has the highest inhibitory activity,IC₅₀=（2.78±0.04）μmol/L,which is about 1.4 times that of OA.（2）.Among the target compounds TM-II series,all the target compounds TM-II-5a～5o show higher inhibitory activities against PTP1B,IC₅₀=[（1.89±0.64）～（16.38±1.94）]μmol/L,and some compounds display higher activities than the control drug OA.Among them,the N-acylhydrazone derivatives containing biscarbazole ring TM-II-5j has the highest activity with IC₅₀value of（1.89±0.64）μmol/L,which is about 0.6 times that of OA.（3）.Among the target compounds TM-III series,all the target compounds TM-III-6～8and TM-III-11 show higher inhibitory activities against PTP1B,IC₅₀=[（0.89±0.06）～（6.14±0.00）]μmol/L.Except for compounds TM-III-6a,TM-III-6b,TM-III-6g and TM-III-6h,the other compounds have higher activities than the control drug OA.Among them,the compound TM-III-11b has the highest inhibitory activity with IC₅₀value of（0.89±0.06）μmol/L,which is about 2.3 times that of OA.3.The bonding mode of representative target compounds TM-I-5t,TM-II-5g,TM-II-5j,TM-III-6d,TM-III-7f and TM-III-11b to the target protein PTP1B are studied by molecular docking.4.The target compounds are potential PTP1B inhibitors.They have potential application in the treatment of cancer and diabetes.The research results of this study provide a powerful basis for the development of novel PTP1B inhibitors.And the research of this thesis is of great significance.