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.