Synthesis And Biological Evaluation Of 3-substituted-4-(Quinoxalin-6-yl)Pyrazoles As Inhibitors Of ALK 5

With the aggravation of environmental pollution,the incidence of cancer is increasing year by year.According to the World Health Organization(WHO)statistics,three fifth of the world’s people die of cancer,diabetes,cardiovascular disease and chronic respiratory diseases,and cancer is the second largest disease to human life in the world.Its mortality is only under cardio-cerebrovascular disease,which is the leading cause of human death.Therefore,the research and development of anti-tumor drugs has been paid more and more attention.So far,drugs with strong the anti-tumor activity and few side effects are still scarce.Transforming growth factor-β(TGF-β)signaling pathway is one of the important pathways for tumor generation and redevelopment.Based on consulting literature,we found that compounds containing thiazole structure have physiological activities such as antibacterial,anticancer,antiviral and antiepileptic,and have good inhibitory activity on ALK5.According to the previous research of this research group,it was found that the derivatives containing quinoxaline and pyrazole moiety showed higher ALK5 inhibition activity and selectivity.Based on the combination principle and biosostere theory,we designed and synthesized a series of compounds(14a-h,15a-h and 16a-h).In order to perform initial screening of the synthesized target compound,a residual activity assay was performed against ALK5 and p38α MAP at 10 μM.All compounds with a 4-methylthiazol-2-yl moiety(14e-h,15-eh,and 16e-h)showed potent ALK5 inhibition activity(27%-98%),whereas those with a 6-(dimethylamino)pyiridin-2-yl moiety(14a-d,15a-d,and 16a-d)showed moderate ALK5 inhibition activity(5%-71%).The amides 14a-d(5%-63%)and 14e-h(95%-97%)showed more potent ALK5 inhibition than their respective positional isomers,15a-d(5%-13%)and 15e-h(27%-54%),respectively.We selected p38α MAP kinase to survey the selectivity profile of this series of compounds.All target compounds except 15e-h(3%-46%)did not inhibit p38α MAP kinase,even at their maximum concentration of 10 μM.To evaluate ALK5 inhibitory activity and selectivity of the targeted compounds,the thioamides 16a-h were selected and their half maximal inhibitory concentration(IC50)values were measured.All compounds with a 4-methylthiazol-2-yl moiety(16e-h)showed potent ALK5 inhibition(IC50=0.28-0.57 μM),whereas those with a 6-(dimethylamino)pyridin-2-yl moiety(16a-d)showed no significant ALK5 inhibitory activity at up to 5.0 μM.Compound 16f showed the most potent ALK5 inhibitory activity with an IC50 value of 0.28 μM in this series of compounds.It was slightly less potent than compounds 3(0.12μM).Compound 16f was the most selective in this series,showing a selectivity index of>35,higher than that of positive control compound 3(4).We examined the binding modes of two representative ligands,16b and 16f using the semi-flexible molecular docking program DS CDOCKER.The results showed that the most active compound 16f showed more favorable intermolecular interactions than compound 16b in the ALK5 active site.In order to check whether the synthesized compound has a medical properties,ADMET prediction is performed on all target compounds.The predicted results indicate that the ADMET parameters of these compounds are within the acceptable range defined for human use and these compounds may exhibit significant pharmacokinetic and drug-likeliness properties.