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, IC50at 1.0 μm against HCT-116, and 3.48 μm against PLC/PRF/5. It is a promising anticancer agent for further development.
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.|Marine Biomedical Research Institute of Qingdao, Qingdao, China.
Yan-Yan
http://orcid.org/0000-0003-2486-050X
YY
Chu
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
He-Juan
HJ
Cheng
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Zhen-Hua
ZH
Tian
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.|Marine Biomedical Research Institute of Qingdao, Qingdao, China.
Jian-Chun
JC
Zhao
Haile PharmaTech Ltd, Jinan, China.
Gang
G
Li
Haile PharmaTech Ltd, Jinan, China.
Yang-Yang
YY
Chu
Haile PharmaTech Ltd, Jinan, China.
Chang-Jun
CJ
Sun
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.|Marine Biomedical Research Institute of Qingdao, Qingdao, China.|Haile PharmaTech Ltd, Jinan, China.
Wen-Bao
WB
Li
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000970:Antineoplastic Agents; D007191:Indazoles; D010671:Phenylurea Compounds; D009536:Niacinamide; D014508:Urea; D000077157:Sorafenib; D019009:Proto-Oncogene Proteins c-kit
anticancer agent; antiproliferative activity; diarylurea derivative; molecular docking; rational drug design