Design, synthesis and broad-spectrum Bcr-Abl inhibitory activity of novel thiazolamide–benzamide derivatives
2019
Liu, Juan | Huang, Honglin | Deng, Xiangping | Xiong, Runde | Caoxuan, | Tang, Guotao | Wu, Xin | Xu, Shiyu | Peng, Junmei
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 (¹H 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 μM and showed inhibition to the T315I mutant with IC₅₀ value 39.89 μM. 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.
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