Synthesis of novel series of pyrazolo[1,5-a]pyrimidines target PIM-1 kinase

Abstract

PIM-1 has emerged as a promising target for the creation of therapeutic agents aimed at treating conditions marked by abnormal cell proliferation, especially cancers. This article describes the design, preparation, and assessment of biology of new pyrazolo[1,5-a] pyrimidines that specifically target PIM-1 kinase. Each of the novel compounds was verified for antineoplastic action in vitro using two colon cancer cell lines, namely HT29 and HCT-116. On the examined cells, the derivatives 3b, 3 g-j showed a strong antitumor activity. Compound 3h exhibited the highest bioactivity against the HCT-116 cell line (IC₅₀ = 3.02 µM), while its IC₅₀ value equals 2.67 µM towards HT29 cell line. Consequently, the most powerful derivative 3h was preferred for additional analysis of its inhibitory potential on PIM-1 kinase, it demonstrated a substantial inhibitory influence on PIM-1 with an IC₅₀ of 0.87 μM. Furthermore, this compound exhibited a high selectivity index and was less harmful to normal cells, WI38. In addition, apoptosis induction potential of 3h was calculated using a few apoptosis markers. Interestingly, relative to the control, it amplified the amount of Bax by 5.7 times, decreased the level of Bcl-2 by 0.3 times and raised the p53 level 6.4 times, suggesting that it may be able to trigger apoptosis. The goal of the molecular docking was to forecast how the target compound 3h will attach to the PIM-1 binding site.