Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide–benzamide derivatives

Bcr-Abl plays an important role in the pathogenesis and development of chronic myeloid leukemia (CML). But Bcr-Abl is prone to mutation, so it increases the difficulty of clinical treatment. Therefore, it is crucial to design a new class of broad-spectrum Bcr-Abl inhibitors. Herein, forty novel thiazolamide-benzamide derivatives were synthesized and evaluated their broad-spectrum Bcr-Abl inhibitory activities. The newly synthesized compounds were characterized by using spectrum data (H-1 NMR, APCI-MS and IR) and elemental analysis. The protein kinase results indicated that eight compounds (3a, 3e, 3m, 3n, 3p, 4c, 4f, 4g) showed high activities to wild-type and T315I mutation. The most potent compound 3m exhibited an Abl IC50 value as low as 1.273 mu M and showed inhibition to the T315I mutant with IC50 value 39.89 mu M. 3m could prove to be a new promising lead compound for the further development of broad-spectrum Bcr-Abl inhibitors to overcome clinical acquired resistance.