Synthesis And Antitumor Activity Evaluation Of Benzothiazole And Thiophene Pyrazole Derivatives

Globally,nearly one in six deaths is caused by malignant tumors.The research of anti-tumor drugs has also been developing rapidly in recent years,and many new types of anti-tumor drugs have emerged,acting on different links and new targets for the occurrence and metastasis of tumors.In China,the incidence of cancer has also been rising year by year with an annual growth rate of 10%.Moreover,it is worth noting that the number of cancers in China accounts for about one-fifth of the world’s incidence,and the number of cancer deaths accounts for about a quarter of the global total.The most common cancers are liver cancer,gastric cancer,liver cancer,colorectal cancer,and breast cancer in China.Therefore,the research and development market for anti-tumor drugs has to be vigorously developed.The development of anti-tumor drugs has further become one of the hot spots in the pharmaceutical industry.Currently discovered anti-tumor drugs mainly target kinases,receptors,and proteins.Among the anti-tumor discovery drugs,anti-cancer protein kinase inhibitors are the most common.Among them,TGF-β inhibitors are also an important part of anti-tumor kinase drugs,which are involved in the re-development of tumors and produce one of the important signaling pathways.In this paper,it is found that the derivatives with benzothiaozole and thiophene structure have good TGF-β inhibition activity and show great potential.According to the previous research of this research group,pyrazole compounds have good TGF-βinhibition activity and selectivity.Accoridng to the combination principle and biosostere theory,we designed and synthesized two series of compounds containing thieno[3,2-c]pyridin-2-yl and benzo[c][1,2,5]thiadiazol-5-yl moiety,and their residual activity were evaluated at 10 μM.All of the two seires of compounds showed good ALK5 inhibition activity in that concentration.In addition to the positional isomers(24a-d and 24e-h).the inhibitory activity of other compounds on ALK5 kinase was 98%-100%.At a maximum concentration of 10 μM,all target compounds showed moderate inhibition(0%-66%)against p38a MAP kinase.To evaluate ALK5 inhibitory activities and selectivity of the compounds possessing benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]pyridin-2-yl moiety,the amides(23a and 23e-h)and the thioamides(25a-d)were selected in view of residual activity and previous data,and their half maximal inhibitory concentration(IC50)values were also measured.The compound 25c(IC50=0.03 μM)showed the highest ALK5 inhibitory activity in these two series of compounds and was 4-fold more potent than the positive control compound 9(IC50=0.119 μM),and the selectivity index of 25c is 235.In these two series,its selectivity index is much higher than 9(4).To explain the differences in the inhibitory activity of two series compounds,we examined the binding modes of two representative ligands,23g and 25c using the semi-flexible molecular docking program DS LibDock.The results further provided theoretical basis for better activity of 25c than 23g.ADMET predictions for all target compounds indicate that other 23 series and 25 series compounds may be well-absorbed compounds except 23d and 25d,which have a strong potential for systemic tumor therapy.