Discovery of N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives as potential antiproliferative agents by inhibiting MEK

Bioorg Med Chem. 2016 Oct 1;24(19):4652-4659. doi: 10.1016/j.bmc.2016.08.002.

Xian-Hai Lv ¹, Zi-Li Ren ², Ben-Guo Zhou ², Qing-Shan Li ³, Ming-Jie Chu ⁴, Dao-Hong Liu ⁴, Kai Mo ⁴, Li-Song Zhang ⁴, Xiao-Kang Yao ⁴, Hai-Qun Cao ⁵

Affiliations

1 School of Science, Anhui Agricultural University, Hefei 230036, PR China; School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China.
2 School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China.
3 School of Medical Engineering, Hefei University of Technology, Hefei 230009, PR China.
4 School of Science, Anhui Agricultural University, Hefei 230036, PR China.
5 School of Plant Protection, Anhui Agricultural University, Hefei 230036, PR China. Electronic address: haiquncao@163.com.

PMID: 27515719 DOI: 10.1016/j.bmc.2016.08.002

Abstract

Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and Cancer development. MEK Inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRaf Inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26μM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.

Keywords

Anti-cancer activity; Inhibitors; MEK; Molecular docking; Pyrazole; QSAR.

Name
Email *

	Sorry, but the email address you supplied was invalid.