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

• Published in: European journal of medicinal chemistry Vol. 168; pp. 315 - 329
• Main Authors: Zeidan, Mohamed A., Mostafa, Amany S., Gomaa, Rania M., Abou-zeid, Laila A., El-Mesery, Mohamed, El-Sayed, Magda A. -A., Selim, Khalid B.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 15-04-2019
• Subjects: A549; Apoptosis; Binding DFG motif; Cell cycle analysis; Kinase inhibition; Picolinamide; VEGFR-2; Picolinamide; Kinase inhibition; VEGFR-2; A549; Cell cycle analysis; Binding DFG motif; Apoptosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.02.050

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.