Design, Synthesis, and 2D QSAR Analysis of Some Novel Pyrazolo[1,5-a]pyrimidine Derivatives as Pim-1 Kinase Inhibitors for the Treatment of MCF-7 Breast Cancer.

In the current study, new pyrazolo [1,5-a]pyrimidine-3-carbonitriles were synthesized and evaluated for their inhibitory activity against Pim-1 kinase. The most potent inhibitors were 4d, 5d, and 9a with IC values (0.61, 0.54 and 0.68 μM) compared to quercetin (IC = 0.91 μM), with some selectivity towards Pim-1 and Pim-3 over Pim-2. Compound 4d exhibited a 1.5-fold increased cytotoxic activity compared to doxorubicin against the MCF-7 cell line, whereas compound 9a showed an analogous activity to doxorubicin. Furthermore, compounds 4d, 5d, and 9a arrested the cell cycle at G2-M phase with a decrease in the G1-phase population. Compounds 4d, 5d, and 9a induced apoptosis in MCF-7 cells by a 94-, 64-, and 78-fold increase in the entire apoptotic and necrotic cells compared to the untreated control cells and increased the levels of wild p53 in MCF-7 cells by 6.5, 6, and 5.7-fold indicating that these compounds may induce apoptosis via increasing the expression level of p53. Moreover, a promising safety profile was shown for compound 4d on MCF-10A normal breast cells. Besides, docking of the desired compounds into Pim-1 ATP binding site showed a noteworthy binding mode for the enzyme inhibition. Additionally, a 2D QSAR identified the potential structural features controlling the Pim-1 inhibitory activity attained via the targeted pyrazolo[1,5-a]pyrimidines.