Synthesis And Biological Activities Of Novel 1,3,5-triazine-triazolothia-diazole-1H-pyrazole Derivatives/Multi-heterocyclic Molecules Of Pyrazole Docking With 1,3,5-triazine And 1,3,4-oxadiazole Derivatives

The biological activities and important applications of derivatives which pyrazole,1,3,5-triazine,triazolothiadiazole and 1,3,4-oxadiazole were used as core skeletons were reviewed.Cdc25B and PTP1B belong to the same class of protein tyrosine phosphorylase(PTP).It is of great significance to find excellent active Cdc25B and PTP1B inhibitors which would be used as anti-cancer and anti-diabetes drugs.Therefore,pyrazole which had excellent pharmacological activities was used as the key skeleton in this paper,connecting1,3,5-triazine,introducting triazolothiadiazole and 1,3,4-oxadiazole in the structures,meanwhile,the morpholine,piperidine and pyrolidine were constructed respectively in one molecule.Thirty-nine novel target compounds were first designed and synthesized and their structures were characterized.The inhibitory activities of the target molecules against Cdc25B and PTP1B were evaluated to screen out the potential inhibitors of Cdc25B and PTP1B,which laid the foundation for the study of anti-cancer and anti-diabetes drugs.In this paper,seventy-nine compounds were synthesized,in which 49 compounds were synthesized for the first time,including 39 target compounds and 10 important intermediates.The structures of the synthetic compounds were characterized by IR,¹H NMR and HRMS.In the first series compounds,twenty–one novel molecules of 1,3,5-triazine-triazolothia-diazole-1H-pyrazol derivatives(TZPT 1-21)were designed and synthesized.In the process,1,3,5-triazine was modified by morpholine,piperidine and pyrrolidine respectively,and then pyrazole containing ester group was constructed through the reaction of Vilsmeier-Haack.The carboxyl-containing important intermediate(TZPA 1-3)were afforded by hydrolysis.Finally,triazolothiadiazole ring was obtained by the cyclization TZPA 1-3 with different1,2,4-triazole(AT 1-5,HT 1-2).In the second series compounds,1,3,5-triazine-disubstituted(morpholine/piperidine/pyrrolidine)-1H-pyrazole-4-carboxylic acid(TZPA 1-3)reacted with different aromatic benzoyl hydrazine(AH 1-6)under heating conditions and in the present of POCl₃to yield 18novel 1,3,5-triazine and 1,3,4-oxadiazole derivatives(TZPO 1-18),in which pyrazole was used as bridge.The inhibitory activities of TZPT1-21 and TZPO 1-18 against Cdc25B and PTP1B were evaluated and the excellent inhibitors of Cdc25B and PTP1B were found.The first series of TZPT 1-21 behave excellent Cdc25B and PTP1B inhibitory activities.In the Cdc25B inhibitory activity test,14 target compounds have higher inhibitory activities than positive reference sodium orthovanadate(IC₅₀=1.86±0.24?g/m L),which are expected to be potential inhibitors of Cdc25B.In the PTP1B inhibitory activity test,9 target compounds have better inhibitory activities than the control of oleanolic acid(IC₅₀=1.25±0.09?g/m L),which are expected to be potential inhibitors of PTP1B.The second series of TZPO 1-18 also behave good Cdc25B and PTP1B inhibitory activities.In the Cdc25B inhibitory activity test,9 target compounds have higher inhibitory activities than positive reference sodium orthovanadate(IC₅₀=1.86±0.24?g/m L),which are expected to be potential inhibitors of Cdc25B.In the PTP1B inhibitory activity test,9target compounds have better inhibitory activities than the control of oleanolic acid(IC₅₀=1.25±0.09?g/m L),which are expected to become potential inhibitors of PTP1B.