Chemical Biology and Drug Design
Chemical Biology and Drug Design
4 years ago

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

Rational drug design of indazole-based diarylurea derivatives as anticancer agents
Wen-bao Li, Chang-jun Sun, He-juan Cheng, Zhen-hua Tian, Gang Li, Yang-yang Chu, Yan-yan Chu, Jian-chun Zhao
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.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12984

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