Rational drug design of indazole‐based diarylurea derivatives as anticancer agents

A series of novel indazole‐based diarylurea derivatives targeting c‐kit were designed by structure‐based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT‐116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT‐116. The structure–activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N ‐(2‐(pyrrolidin‐1‐yl)ethyl)‐carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC 50 at 1.0 μ m against HCT‐116, and 3.48 μ m against PLC/PRF/5. It is a promising anticancer agent for further development.