Synthesis, activity and docking studies of phenylpyrimidine–carboxamide Sorafenib derivatives

Publication date: 1 December 2016
Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 23
Author(s): Wenhui Wang, Chunjiang Wu, Jianqiang Wang, Rong Luo, Caolin Wang, Xiaobo Liu, Jiqing Li, Wufu Zhu, Pengwu Zheng
Two series of Sorafenib derivatives bearing phenylpyrimidine–carboxamide moiety (16a–g and 17a–p) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, MCF-7 and PC-3). Two selected compounds (17f and 17n) were further evaluated for the activity against VEGFR2/KDR kinase. More than half of the synthesized compounds showed moderate to excellent activity against three cancer cell lines. Compound 17f showed equal activity to Sorafenib against MCF-7 cell line, with the IC50 values of 6.35±0.43μM. Meanwhile, compound 17n revealed more active than Sorafenib against A549 cell line, with the IC50 values of 3.39±0.37μM. Structure–activity relationships (SARs) and docking studies indicated that the second series (17a–p) showed more active than the first series (16a–g). What's more, the introduction of fluoro atom to the phenoxy part played no significant impact on activity. In addition, the presence of electron-donating on aryl group was benefit for the activity.

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