Synthesis And Biological Evaluation Of Novel Benzo[c][1,2,5] Thiadiazol-5-yl And Thieno[3,2-c]-Pyridin-2-yl Imidazole Derivatives As ALK5 Inhibitors

At this stage,with the development of the world economy,environmental pollution has increased,and the incidence of malignant tumors has increased year by year.According to the latest statistics from the World Health Organization(WHO),there are approximately 18.1 million new cancer cases and 9.6 million cancer deaths worldwide in 2018 and the cancer has become the world’s second-largest disease after cardiovascular and cerebrovascular diseases.The clinical treatment of tumors mainly includes radiotherapy and chemotherapy as well as surgical treatment.Chemotherapy is currently the most common treatment.Therefore,the development of anti-tumor drugs has also become one of the hot spots in the pharmaceutical industry.The current chemotherapy drugs have been greatly improved in terms of activity compared to the original chemotherapy drugs,but most of them have the disadvantage of poor selectivity.During the course of chemotherapy,the normal cells of the human body are also damaged while killing the cancer cells,resulting in serious adverse drug reactions,which ultimately lead to poor treatment or even failure.Therefore,the development of new anti-tumor drugs with strong anti-tumor activity and small side effects is currently the common goal.At present,the new anti-tumor drugs mainly focus on targeted therapy,and the main targets are kinases,receptors and proteins.Among them,transforming growth factor-β(TGF-β)signaling pathway targeting activin receptor-like kinase 5(ALK5)is one of the important pathways for tumor production and development.Therefore,ALK5 inhibitors are an important component of anti-tumor drugs.Transforming growth factor-β(TGF-β)is a key mediator of tumor growth and metastasis,and ALK5 is one of the important receptors in the TGF-β signaling pathway.Therefore,ALK5 has been recognized as an important tumor drug target.According to the research of the previous group of the research group,it was found that the compound containing the imidazole structure has good ALK5 inhibitory activity and selectivity.According to the combination and electronic isosteric principle,two series of compounds containing benzo[c][1,2,5]thiadiazol-5-yl imidazoles(27a-g)and thieno[3,2-c]-pyridin-2-yl imidazoles(33a-g)were designed and synthesized.Their inhibitory activities against active receptor-like kinase 5(ALK5)and p38α mitogen-activated protein(MAP)kinase were evaluated in an enzymatic assay.All the two series of compounds showed better ALK5 inhibitory activity.Among them,compound 27c had the highest inhibitory activity against ALK5 kinase,and its IC50 value was 0.008 μM.The inhibitory activity of 27c was 16.1 and 1.8 times,respectively,of the positive control compounds LY-2157299(IC50=0.129μM)and EW-7197(IC50=0.014 μM).Compound 27g has the highest selectivity index for p38α MAP kinase of 350,which is much higher than the selectivity of the positive control compounds LY-2157299(4)and EW-7197(211).The inhibitory effects of compound 27c on TGF-β-induced Smad signaling and cell motility were investigated in SPC-A1,HepG2 and HUVEC cells using western blot analysis and wound healing assays.ADMET prediction analysis showed that compounds 27c and 27g had good pharmacokinetic and drug-likeness behaviors.