Synthesis and evaluation of c-Src kinase inhibitory activity of pyridin-2(1H)-one derivatives

• Eighteen novel 2-pyridones were synthesized and characterized from spectral data.
• These compounds were screened for c-Src kinase inhibition.
• Eight compounds exhibited IC50 ⩽ 25 μM for Src kinase inhibition.
• Antiproliferative activity of compounds were screened against 3 cancer cell lines.
• Results can be used to design next generation of 2-pyridones as Src kinase inhibitors.

Src kinase, a prototype member of the Src family of kinases (SFKs), is over-expressed in various human tumors, and has become a target for anticancer drug design. In this perspective, a series of eighteen 2-pyridone derivatives were synthesized and evaluated for their c-Src kinase inhibitory activity. Among them, eight compounds exhibited c-Src kinase inhibitory activity with IC50 value of less than 25 μM. Compound 1-[2-(dimethylamino)ethyl]-5-(2-hydroxy-4-methoxybenzoyl)pyridin-2(1H)-one (36) exhibited the highest c-Src kinase inhibition with an IC50 value of 12.5 μM. Furthermore, the kinase inhibitory activity of compound 36 was studied against EGFR, MAPK and PDK, however no significant activity was observed at the highest tested concentration (300 μM). These results provide insights for further optimization of this scaffold for designing the next generation of 2-pyridone derivatives as candidate Src kinase inhibitors.

Among eighteen pyridin-2(1H)-one derivatives synthesized, compounds 36 and 38 were found to be the most potent c-Src kinase inhibitors with IC50 values of 12.5 μM and 19.9 μM, respectively.Figure optionsDownload as PowerPoint slide