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

Abstract: 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 con-densation, 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 cou-marin 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 hydro-phobicity 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