Synthesis And Activity Evaluation Of Amide Sulfides Bridged With1,3-Selenazole And 1,2,4-Triazole Derivatives

In this paper,the synthesis and excellent biological activities of the active block compounds including 1,3-selenazole,1,3-thiazole,1,2,4-triazole and their schiff bases are reviewed in recent years.Cdc25B and PTP1B can be used as therapeutic targets for cancer and diabetes respectively.Because to screen Cdc25B and PTP1B inhibitors with excellent activity,the first time in the paper through amide sulfides bond,1,3-selenazole ring and1,2,4-triazole schiff base were bridged.Thirty novel target molecules are designed,synthesized and characterized.Using the target molecules,the inhibitory activities against Cdc25B and PTP1B were tested,The molecular docking simulations were performed using two representative target molecules STSE 1 and STSE 28 with Cdc25B and PTP1B respectively.The molecular docking simulation with Cdc25B and PTP1B was carried out by using MOE software,and the mode of interaction between the inhibitors and the active sites on the two enzymes was determined.1.Thirty novel target molecules were designed and synthesized for the first time by a convergent synthesis method,and their structures were characterized and confirmed by IR,NMR and so on.In the process of synthesis,on the one hand,selenium powder was used as starting materials,4-phenyl-2-amino-1,3-selenazole（SZ）were synthesized through by reduction,addition,substitution and cyclization.On the other hand,when three aromatic acids were used as the starting material to afford the aromatic 1,2,4-triazole（PTZ 1-3）through by esterification and cyclization,when two fatty acid were used as the starting materials to afford the fatty 1,2,4-triazole（FTZ 1-2）through by melting method.Then PTZ 1-3 and FTZ 1-2were condensed with six different aromatic aldehydes to form the 1,2,4-triazole schiff bases（TZS 1-30）.Finally,thirty new amide sulfides bridged with 1,3-selenazole and1,2,4-triazole derivatives（STSE 1-30）were obtained by using amide sulfides to bridge the schiff base（TZS 1-30）with 4-phenyl-2-amino-1,3-selenazole（SZ）.2.To screen Cdc25B inhibitors with excellent activity and to confirm the rationality of the overall structure design of target molecules,the inhibitory activities of target molecules and important intermediates on Cdc25B were compared and tested.The result show that the inhibitory activities of intermediates were not excellent and the inhibition rates of 29 target molecules are more than 92%,in which 25 target molecules are higher than that of the positive reference Na₃VO₄(IC₅₀=1.86±0.24μg/m L),which are likely to be the Cdc25B inhibitors.At the same time,the target molecules and important intermediates were used to test the inhibitory activities of PTP1B.The result show that the inhibition rates of 29 target molecules are more than 82%,in which 7 target molecules are higher than that of the positive reference group Oleanolic acid(IC₅₀=1.30±0.01μg/m L),which are also likely to be the PTP1B inhibitors.3.In order to study the patterns used by target molecules to interact with Cdc25B and PTP1B respectively,we can better analyze the possible causes of inhibitory activity,the molecular docking simulations of STSE 1 and STSE 28 with Cdc25B and PTP1B were carried out respectively.Cdc25B docking results of STSE 1 show that oxygen atom of the carbonyl group interacts with the hot spot residue Arg488 and Arg492 to form hydrogen bonds.Cdc25B docking results of STSE 28 show that oxygen atom of carbonyl group and selenium atom with the hot spot residue Arg492 forms hydrogen bonds respectively.PTP1B docking results of STSE 1 show that selenium atom hydrogen with the activity site Asp48forms hydrogen bond;selenazole ring with Tyr46 formsπ-H interaction;the 1,2,4-triazole ring with Lys120 formsπ-cation interactions;benzene ring of the schiff base with Ala217formsπ-H interaction.PTP1B docking results of STSE 28 show that selenium atom with the Asp181 amion acid forms a hydrogen bond.the oxygen atom of the carbonyl group with the main catalytic action Arg221 forms a hydrogen bond and the hydroxy group on the benzene ring with the activity site Asp48 forms a hydrogen bond.The above results show that the different active blocks in the target molecular structure interact strongly with Cdc25B and PTP1B respectively（hydrogen bond）,which indicates that the overall structure design of the target molecule is reasonable and the active superposition is realized.Moreover,the theoretical simulation results coincided with the experimental results of inhibitory activity,and the potential inhibitors of Cdc25B and PTP1B were screened,which provided an important reference for the research and development of anti-cancer and anti-diabetes drug precursors,and achieved the expected research purpose.