Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities

Abstract

New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds <b>5b</b>, <b>5c</b>, <b>6e, 13a</b>, <b>13c,</b> and <b>14a</b> showed <i>in-vitro</i> low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent <i>in-vitro</i> anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, <b>6e, 13a,</b> and <b>13c</b> significantly induced apoptosis with percentage more than 66%. Moreover, <b>6e, 13a,</b> and <b>13c</b> significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, <b>5c, 6e,</b> and <b>14a</b> showed potent <i>in-vitro</i> PIM-1 kinase inhibitory activity. While, <b>5b</b> showed potent <i>in-vitro</i> PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver-Burk double-reciprocal plot indicated that <b>5b</b>, <b>5c</b>, <b>6e,</b> and <b>14a</b> behaved as competitive inhibitors while <b>13a</b> behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, <i>in-silico</i> affinity came in coherence with the observed <i>in-vitro</i> inhibitory activities against PIM-1/2 kinases.