Synthesis And Cdc25B/PTP1B Activity Evaluation Of Novel Benzimidazole-Acylhydrazone And 2,5-Disubstituted-1,3,4-Thiadiazole Amide Derivatives Containing Carbazole/Benzimidazole Moiety

1.In this paper,twenty-six novel target compounds,fourteen benzimidazole-acylhydrazone derivatives(TM-?-7a?7n)and twelve 2,5-disubstituted-1,3,4-thiadiazole amide derivatives containing carbazole/benzimidazole moiety(TM-?-5a?5g and TM-?-7a?5e),were designed and synthesized.The structures of the target compounds were characterized by IR?NMR?MS spectra and elemental analyses.2.The inhibitory activities of the target compounds TM-I-7a?7n against Cdc25B and PTP1B were evaluated.The inhibitory activities of the target compounds TM-?-5a?5g and TM-?-7a-7e against PTP1B were also evaluated.The results are as follows:?In the target compounds TM-?-7a?7n series,most of them exhibited good inhibitory activities against Cdc25B/PTPlB.Among them,compounds TM-?-7f and TM-?-7n containing 9-alkylcarbazole moiety were most potent with IC50 values of(0.27+0.04)?g/mL and(1.75±0.29)?g/mL for Cdc25B and PTP1B,respectively.It is noteworthy that the target compound TM-?-7n had good inhibitory activities against Cdc25B and PTP1B.?In the target compounds TM-?-5a?5g and TM-?-7a?7e series,they had high inhibitory activities against PTP1B(except for TM-?-7d and TM-?-7e),IC50=(2.43?20.49)?g/mL.Among them,the inhibitory activities of the compounds TM-?-5b and TM-II-5c against PTP1B were higher than the positive control drug oleanolic acid,IC50 values were(2.69±0.24)?g/mL and(2.43±0.43)?g/mL,respectively.And the activity of the compound TM-II-5d was comparable to the control drug.3.The bonding patterns of representing the target compounds with the target protein were studied by molecular docking and DFT calculation.The results showed that the target compounds TM-?-7f and TM-?-7n were linked to the active sites of Cdc25B and PTP1B,and formd stable complexes with Cdc25B/PTP1B enzyme.The inhibition against Cdc25B/PTP1B were mainly caused by the hydrogen bond between the acylhydrazone group and the carbazole ring with the target proteins.And the target compound TM-?-5c can enter the center of the active site of enzyme and formd a stable complex with PTP1B enzyme.The inhibition against PTP1B was mainly caused by the hydrogen bond between the thiazolamide group and the carbazole ring with the target protein.4.The obtained research results in this paper will provide important basis for the development of novel Cdc25B and PTP1B inhibitors in the treatment of cancer and diabetes.The research of this thesis is of important significance.