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

Abstract

ABSTRACT 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 50 values (0.61, 0.54 and 0.68 μM) compared to quercetin (IC 50 = 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.