Design, synthesis and molecular modeling of new coumarin-thiazole derivatives as dual EGFR/HDAC1 inhibitors: in vitro and in vivo anticancer assays

Abstract

The growing evidence ascertaining the overexpression of EGFR and HDAC1 in breast and colorectal cancers prompted us to design and synthesize some new coumarin-thiazole derivatives with dual EGFR/HDAC1 inhibitory activity, considering the nature of EGFR and HDAC inhibitory models. The new derivatives were evaluated for their in vitro cytotoxicity against HCT-116 and MCF-7 cancer cells along with BJ-1 normal cells. Compound 3-(-1-((-5-(-(4-bromophenyl)diazenyl)-4-methylthiazol-2(3H)-ylidene)hydrazono)ethyl)-4-hydroxy-2H-chromen-2-one (3m) showed promising selectivity indices for both cell lines, preferential inhibition of EGFR/HDAC1/ERK, induction of cell cycle arrest and apoptosis, and significant in vivo antitumor activity against Ehrlich ascites and solid carcinoma models. Docking study showed that the selected compound attained promising results within the active sites of EGFR and HDAC1.