Synthesis And Biological Activity Study Of Novel Heterocyclic Modified 1,3,4-Oxadiazole Sulfidamide Derivatives

Cdc25B and PTP1B are members of the protein tyrosine phosphatase family.They are the promising targets for anti-cancer and anti-diabetic treatment,respectively.It is great of significance for developing the inhibitors against Cdc25B and PTP1B based on the action sites between the inhibitors with Cdc25B and PTP1B,and thus screen the lead compounds of anti-cancer and anti-diabetic drugs.In this paper,1,3,4-oxadiazole which had anti-cancer and anti-diabetic pharmacological activities was used as the key skeleton and combined with1,3,4-thiadiazole and 1,3,5-triazine active blocks.Morpholine,pyrrolidine and piperidine active heterocyclic were also constructed in the target molecules.As a result,eighteen novel multi-heterocyclic 1,3,4-oxadiazole thioether amide derivatives are first designed and synthesized and the structures of all the compounds are characterized.On the other hand,the inhibitory activities of the target molecules against Cdc25B and PTP1B have been evaluated,the results show that the novel target molecules express excellent inhibitory activities against Cdc25B and PTP1B.1.Forty-five compounds were synthesized through a series of classic reactions,in which25 unreported compounds including 18 target molecules and 7 intermediates.Their structures were confirmed by IR,NMR and HRMS.The nucleophilic substitution reactions of cyanuric chloride with morpholine,pyrrolidine and piperidine respectively were performed;the1,3,4-oxadiazole 5(a-c)containing mercapto group were constructed through the reactions of coupling reaction,esterification,hydrazidation and cyclization.Under alkaline condition,5(a-c)were docked with the intermediates CSA(1-6)to afford 18 new target compounds TZOA 1-18.2.The inhibitory activities of the related intermediates and synthetic target compounds against Cdc25B and PTP1B were tested respectively.The results of the inhibitory activities against Cdc25B show that few intermediates have inhibitory activities,but most target compounds have significant inhibitory activities,8 target molecules TZOA 11-18 have higher inhibitory activities than positive reference sodium orthovanadate(IC₅₀=1.28±0.11?g·m L^-1),in which TZOA 18 has the optimal inhibition,its IC₅₀value is 0.46±0.34?g·m L^-1.In the PTP1B inhibitory activity test,few intermediates show inhibitory activities,but most target compounds generally behave better inhibitory activities,in which TZOA 11 has the optimal inhibition,its IC₅₀ value is 2.37±0.38?g·m L^-1.This result shows that when 1,3,4-oxadiazole,1,3,5-triazine and 1,3,4-thiadiazole are combined compatibly,the biological activities of the target compounds tend stengthen according to the active superposition principle,then the intended purpose of the experiment is achieved.3.Docking studies were performed by placing compounds TZOA-13 and TZOA-18 into the active sites of Cdc25B and PTP1B.The results show that the target molecules interact with the most important active sites in Cdc25B and PTP1B.The results of the target compounds inhibitory activities against Cdc25B and PTP1B are consistent with that of molecules docking simulations,which indicate that the target molecules are well-designed and can be used as potential inhibitors of Cdc25B and PTP1B.