Benzoxazole/benzothiazole‐derived VEGFR‐2 inhibitors: Design, synthesis, molecular docking, and anticancer evaluations
- 9 October 2019
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 352 (12), e1900178
- https://doi.org/10.1002/ardp.201900178
Abstract
A novel series of benzoxazole/benzothiazole derivatives 4a–c–11a–e were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 4c was found to be the most potent derivative against HepG2, HCT‐116, and MCF‐7 cells, with IC50 values = 9.45 ± 0.8, 5.76 ± 0.4, and 7.36 ± 0.5 µM, respectively. Compounds 4b, 9f, and 9c showed the highest anticancer activities against HepG2 cells with IC50 values of 9.97 ± 0.8, 9.99 ± 0.8, and 11.02 ± 1.0 µM, respectively, HCT‐116 cells with IC50 values of 6.99 ± 0.5, 7.44 ± 0.4, and 8.15 ± 0.8 µM, respectively, and MCF‐7 cells with IC50 values of 7.89 ± 0.7, 8.24 ± 0.7, and 9.32 ± 0.7 µM, respectively, in comparison with sorafenib as reference drug with IC50 values of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 4a–c, 9b,c,e,f,h, and 11c,e were further evaluated for their VEGFR‐2 inhibition. Compounds 4c and 4b potently inhibited VEGFR‐2 at IC50 values of 0.12 ± 0.01 and 0.13 ± 0.02 µM, respectively, which are nearly equipotent to the sorafenib IC50 value (0.10 ± 0.02 µM). Furthermore, molecular docking studies were performed for all synthesized compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.Keywords
This publication has 37 references indexed in Scilit:
- Synthesis and Bioactivity Evaluation of New 6-Aryl-5-cyano Thiouracils as Potential Antimicrobial and Anticancer AgentsMolecules, 2012
- Biomarkers in Tumor Angiogenesis and Anti-Angiogenic TherapyInternational Journal of Molecular Sciences, 2011
- Vascular endothelial growth factors and receptors: Anti-angiogenic therapy in the treatment of cancerMolecular Aspects of Medicine, 2011
- Impact of aryloxy-linked quinazolines: A novel series of selective VEGFR-2 receptor tyrosine kinase inhibitorsBioorganic & Medicinal Chemistry Letters, 2011
- Pharmacophore modeling and virtual screening studies for new VEGFR-2 kinase inhibitorsEuropean Journal of Medicinal Chemistry, 2010
- Displacement of disordered water molecules from hydrophobic pocket creates enthalpic signature: Binding of phosphonamidate to the S1'-pocket of thermolysinBiochimica et Biophysica Acta (BBA) - General Subjects, 2010
- More than a Simple Lipophilic Contact: A Detailed Thermodynamic Analysis of Nonbasic Residues in the S1 Pocket of ThrombinJournal of Molecular Biology, 2009
- Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitorsJournal of Enzyme Inhibition and Medicinal Chemistry, 2008
- Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibitionCellular Signalling, 2007
- Discovery and development of sorafenib: a multikinase inhibitor for treating cancerNature Reviews Drug Discovery, 2006