Design, Synthesis and Biological Evaluation of Novel Benzoylimidazole Derivatives as Raf and Histone Deacetylases Dual Inhibitors

摘要

In recent studies, combinations of histone deacetylases (HDACs) inhibitor with kinase inhibitor showed additive and synergistic effects. BRaf(V600E) as an attractive target in many diseases treatments has been studied extensively. Herein, we present a novel design approach though incorporating the pharmacophores of BRaf(V600E) inhibitor and HDACs inhibitor in one molecule. Several synthesized compounds exhibited distinct BRaf(V600E) and HDAC1 inhibitory activities. The representative dual Raf/HDAC inhibitor, 7a, showed better antiproliferative activities against A549 and SK-Mel-2 in cellular assay than SAHA and sorafenib, with IC50 values of 9.11 mu M and 5.40 mu M, respectively. This work may lay the foundation for the further development of dual Raf/HDAC inhibitors as potential anticancer agents.