Synthesis And Cdc25B/PTP1B Inhibitory Activity Evaluation Of Novel Acylthiourea/1,2,4-triazine Derivatives Containing Carbazole Moiety

1.In this paper,twenty-four novel target compounds,fourteen acylthiourea derivatives containing carbazole moiety TM-I-3a~3n and ten 1,2,4-triazine derivatives containing carbazole moiety TM-II-5a~5j,were designed and synthesized.The structures of the target compounds were characterized by IR,1H NMR,13 C NMR and elemental analysis.2.The inhibitory activities of the target compounds TM-I-3a~3n and TM-II-5a~5j against Cdc25 B and PTP1 B were evaluated.The results are as follows:(1)In the target compounds TM-I-3a~3n series,all the compounds showed potent inhibitory activity against Cdc25 B with inhibition rates from 87.94% to 98.78%.Among them,the inhibitory activity of TM-I-3n was the highest,IC50=(0.49±0.12)?g/m L.Partial compounds displayed potent inhibitory activity against PTP1 B.Among them,the inhibitory activity of TM-I-3l was the highest,IC50=(3.59±1.15)?g/m L.It is noteworthy that the target compounds TM-I-3a~3f,3h and 3k~3n have good inhibitory activities against Cdc25 B and PTP1 B.(2)In the target compounds TM-II-5a~5n series,partial compounds showed poten inhibitory activity against Cdc25 B.Among them,the inhibitory activity of TM-II-5i was the highest,IC50=(2.10±0.27)?g/m L.All the target compounds displayed potent inhibitory activity against PTP1 B.Among them,the inhibitory activity of TM-II-5j [IC50=(1.74±0.04)?g/m L] was higher than that of the control drug oleanolic acid [IC50=(1.92±0.02)?g/m L]?It is noteworthy that the target compounds TM-II-5a~5c,5e~5f and 5h~5j have good inhibitory activities against Cdc25 B and PTP1B?3.The molecular docking of representing the target compounds were performed in order to study their bonding mode with the enzyme.Molecular docking simulations demonstrated the target compounds TM-I-3n and TM-I-3l/TM-II-5i and TM-II-5j can bind to active sites of Cdc25B/PTP1 B.4.The obtained research results in this paper will provide important basis for the development of novel Cdc25 B and PTP1 B inhibitors in the treatment of cancer,diabetes and obesity.The research of this thesis is of important significance.