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

• Published in: Chemical biology & drug design 2017-10, Vol.90 (4), p.609-617
• Main Authors: Chu, Yan‐yan, Cheng, He‐juan, Tian, Zhen‐hua, Zhao, Jian‐chun, Li, Gang, Chu, Yang‐yang, Sun, Chang‐jun, Li, Wen‐bao
• Format: Article
• Language: English
• Subjects: anticancer agent; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiproliferative activity; Cell Line, Tumor; Cell Proliferation - drug effects; Computer-Aided Design; diarylurea derivative; Drug Design; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Indazoles - chemistry; Indazoles - pharmacology; molecular docking; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenylurea Compounds - pharmacology; Proto-Oncogene Proteins c-kit - metabolism; rational drug design; Structure-Activity Relationship; Urea - analogs & derivatives; Urea - pharmacology
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12984

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, IC50 at 1.0 μm against HCT‐116, and 3.48 μm against PLC/PRF/5. It is a promising anticancer agent for further development. Based on the structure‐based drug design, we designed and prepared a series of novel indazole‐based diarylurea derivatives targeting c‐kit, and their antiproliferative activities were evaluated. We used molecular docking method to explore the interaction mechanisms and SAR. Compound 1i possessed improved solubilities and best activities. It is a promising anticancer agent and under further development.