Design,Synthesis And Biological Activity Study Of Novel N~1-Substituted Aryloxy-N~3-Substituted Thiazolinone Urea Derivatives

Objective:A series of novel N¹-substituted aryloxy-N³-substituted thiazolinone urea derivatives were designed and synthesized based on the results obtained in our previous study.The structures of target compounds were confirmed,and the biological activities and mechanism were also studied preliminarily.In addition,the structure-activity relationship was analyzed according to the results of biological evaluation.Method:Starting from commercially available 7-?benzyloxy?-4-chloro-6-methoxy-quinoline,semicarbazones were prepared by nucleophilic substitution,deprotection,reduction,acylation,hydrazinolysis and condensation reactions.Treatment of semicarbazones with mercaptoacetic acid afforded the target compounds Z-1^Z-17 and Z-19.Taking 3-hydroxy-4-methoxyacetophenone as starting material,target compound Z-18 was prepared by nucleophilic substitution,nitration,reduction,deprotection,acylation and condensation reactions.The structures of target compounds were confirmed by HRMS and ¹HNMR.The inhibitory activities against c-Met and Ron kinases were determined by mobility assay.Human colon cancer cell line HT-29 was selected and antitumor activities of all target compounds was evaluated by MTT assay.Real-time dynamic live-cell imaging was used to study antitumor mechanism preliminarily,and the toxicity against normal human colonic epithelial cell lines FHC was evaluated meanwhile.Results:Nineteen novel N¹-substituted aryloxy-N³-substituted thiazolinone urea derivatives were designed and synthesized,and their structures were confirmed by HRMS and ¹HNMR.Most compounds show moderate inhibitory activities against c-Met and Ron kinases,which were weaker or equivalent to the positive drug Cabozantinib.Most compounds showed potent in vitro antitumor activity against HT-29 cell lines.Among them,the most potent compound was Z-1 with IC₅₀0 value of 0.31?M against HT-29 cell lines,which was 9.2-and 34.2-time than that of Regorafenib and Cabozantinib,respectively.The results of in vitro kinase profile indicated that compound Z-1 showed moderate inhibitory activities against PDGFR?,AXL,and c-Src kinases.The results of real-time dynamic live cell experiments showed that different concentrations of compound Z-1 could inhibit the proliferation of HT-29 cell lines,and the cytotoxity against HT-29cell lines was more potent than that of Regorafenib.Moreover,the antiproliferation and cytotoxity was in time-and dose-dependent manners.In addition,the antiproliferation and cytotoxity of compound Z-1 against human normal colorectal mucosal cell lines FHC was significantly weaker than that of Regorafenib at different concentrations.Conclusion:Through this study,19 novel N¹-substituted aryloxy-N³-substituted thiazolinone urea derivatives were designed and synthesized,and their structures were confirmed.Moreover,preliminary structure-activity relationships were summarized.The results of biological activities showed that this series of compounds showed moderate inhibitory activities against a variety of kinases,and the in vitro antitumor activity was more potent than that of Cabozantinib and Regorafenib.In addition,the antiproliferation and cytotoxity against normal human colonic epithelial cell lines FHC was weaker than that of Regorafenib,and the results indicated that the toxicity of the novel compounds was weaker.