Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC50 values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC50 = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining. Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. Compounds 7h, 9a and 9l possessed the most significant activity against VEGFR-2 kinase and were further evaluated to measure their possible multi-kinases inhibitory effect against four tyrosine kinases (EGFR, HER-2, c-MET and MER). Further investigations were performed including molecular docking, cell cycle arrest, apoptosis and apoptotic markers. [Display omitted] •Two new series of picolinamides was designed, synthesized and enzymatically evaluated as VEGFR-2 inhibitors.•Cytotoxic activity was assessed against A549 cell lines.•Multikinase inhibitory activities of compounds7h, 9a and 9l towards VEGFR-2, HER-2, c-MET, MER and EGFR were evaluated.•Molecular docking of the most potent VEGFR-2 inhibitors 7h, 9a and 9l was done.•Compound 9a induced apoptosis and showed cell cycle arrest at G2/M phase.