Synthesis and Evaluation of Antitumor Activity of Sorafenib Derivatives Possessing Diphenylamine and Thiourea Structures

17 novel sorafenib derivatives possessing diphenylamine and thiourea structures were designed and synthesized using 2-picolini acid and substituted anilines as raw materials. The structures of the target compounds were all characterized by NMR and HRMS. In addition, the in vitro antiproliferation activity of the target compounds was studied in human colon cancer cell HCT116, human breast cancer cell line MDA-MB-231, human prostate cancer cell line PC-3 and mouse melanoma cell line B16BL6. The results showed that l-(4-chloro-3-trifluoromethylphenyl)-3-(4-(2-(isopropylcarbamoyl)pyridme-4-amino)phenyl)thiourea (9g) had better inhibitory activity against four cell lines than the positive drug sorafenib, and l-(3-trifluoromethyl-4-chlorophenyl)-3-{4-[2-(methylcarbamoyl)pyridine-4-amino]phenyl}thiourea (9b) and l-(3-trifluoromethyl-4-fluorophenyl)-3-{4-[2-(isopropylcarbamoyl)pyridine-4-amino]phenyl} thiourea (9j) had better inhibitory activity against MDA-MB-231, PC-3 and B16BL6 cell lines. The molecular docking of the active small molecule 9j was further studied, and its binding mode with the active site of the 3-D crystal structure (5HI2) of B-Raf receptor was discussed, which provided a useful reference for the design and synthesis of novel sorafenib derivatives in the future.