Design, synthesis and biological evaluation of novel acrylamide analogues as inhibitors of BCR-ABL kinase

A series of acrylamide analogues were designed and synthesized from Imatinib and Nilotinib as novel Bcr-Abl inhibitors by application of the principle of nonclassical electronic isostere. All new compounds were evaluated for their inhibitory effects on the activity of Bcr-Abl kinase and the proliferation of K562 leukemia Cancer cells in vitro. The acrylamide analogues in which the substituent in C ring was trifluoromethyl group were identified as highly potent Bcr-Abl kinase inhibitors. Compound 13f exhibited an IC(50) value as low as 20.6 nM in ABL kinase inhibition and an IC(50) value of 32.3 nM for antiproliferative activity, about 10.5-fold and 12-fold lower than those of Imatinib respectively. These results suggest that compound 13f is a promising candidate as a novel Bcr-Abl kinase inhibitor for further development.