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.
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