Discovery of new pyridine-O-propargyl/1,2,3-triazole hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities

New compounds were designed and synthesized to act as inhibitors of PIM-1 kinase enzyme. Compounds 4b, 6a, 6e and 6i demonstrated significant in vitro Anticancer activity against myeloid leukemia (NFS-60), liver Cancer (HepG-2), prostate Cancer (PC-3), and colon Cancer (Caco-2), with low toxicity toward normal lung fibroblasts (Wi-38). Compounds 4b and 6a effectively induced Apoptosis with more than 60 % in all tested Cancer cell lines using annexin V/propidium iodide analysis. Additionally, compounds 4b, 6a, 6e and 6i caused a notable increase in Caspase activation, exceeding three-fold compared to the reference drug. The inhibitory activity against PIM-1 kinase was potent for all four compounds. Kinetic studies, represented by Lineweaver-Burk double-reciprocal plots, revealed that compounds 4b and 6e as well as quercetin are mainly behaved as competitive inhibitors of the PIM-1 kinase enzyme. Conversely, compounds 6a and 6i exhibit both competitive and non-competitive inhibition of PIM-1 kinase enzyme.

Anticancer; Apoptosis induction; Caspase 3/7 activation; PIM-1 kinase inhibitors; Pyridine.