Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors

Abstract

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC₅₀ of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18 μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC₅₀ values.

Keywords:

• Pyridothienopyrimidine
• pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one
• cytotoxic activity
• pim-1 inhibitors

Acknowledgements

The authors are grateful to Kinexus lab, Canada, for performing the kinase inhibitory assays.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.