Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
Email: lddd@benthamscience.org


Synthesis and Biological Evaluations of 3-Benzothiazol-2-yl Coumarin Derivatives as MEK1 Inhibitors

Author(s): Chao Wang, Fengrong Xu, Yan Niu, Yun Wu, Jing Sun, Yihong Peng, Lei Liang, Ping Xu.


In order to discover novel MEK inhibitors, a series of 3-(benzothiazol-2-yl) coumarin derivatives have been synthesized following our earlier study of 3-benzyl coumarin derivatives. The target compounds were obtained by condensation, cyanation, hydrolyzation and esterification starting from o-hydroxy benzaldehydes and benzothiazole-2- acetonitrile. The cyanation reaction could only occur when there were electron with drawing groups at C3 position of coumarin scaffold. All the synthesized compounds showed weak binding and inhibition potencies to phosphorylated MEK1 but obvious inhibitory effect to unphosphorylated MEK1, suggesting that compounds inhibition to MEK1 is mainly due to the inhibition of npMEK1 rather than pMEK1. The most potent compound 3 was with an inhibition rate of 60.7% at 1 μM in the RAF-MEK cascading assay. Molecular docking studies revealed that the pocket occupation and structure hydrophobicity may be important for activity. These results can contribute to further optimization on coumarin scaffold and led to the design of novel coumarin derivatives as more potent MEK1 inhibitors.

Keywords: Benzothiazolyl, Coumarin, Cyanation, Dock, MEK inhibitor, Unphosphorylated MEK1.

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

Year: 2013
Page: [727 - 732]
Pages: 6
DOI: 10.2174/15701808113109990012
Price: $58