Thiazolyl N-benzyl-substituted acetamide derivatives: Synthesis, Src kinase inhibitory and anticancer activities

KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure–activity relationship, a number of N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI50 values of 1.34 μM and 2.30 μM in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. 4-Fluorobenzylthiazolyl derivative 8b exhibited 64–71% inhibition in the cell proliferation of BT-20 and CCRF cells at concentration of 50 μM.

Graphical abstractA number of N-benzyl substituted (2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives were synthesized and their Src kinase inhibitory and anti-proliferation activities of the conjugates were evaluated and compared in leukemia, breast, and colon cancer cell lines.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A number of N-benzyl-substituted acetamide derivatives were synthesized. ► The compounds were evaluated as Src kinase inhibitors and anticancer agents. ► The unsubstituted N-benzyl derivative was the most potent Src kinase inhibitor. ► 4-Fluorobenzylthiazolyl derivative inhibited the proliferation of breast cancer.