Design, synthesis and evaluation of the 2′-hydroxy-3′-iodo-5′-nitrochalcones for cytotoxicity (MCF-7 & A549) and potential to inhibit tyrosine kinase (VEGFR-2) activity

Abstract

A series of the 2-hydroxy-3-iodo-5-nitrochalcones 3a–n was synthesized and characterized spectroscopically (FT-IR, ESI-MS, 1H-NMR, and 13C-NMR) complemented with single crystal X-ray diffraction analysis. The compounds were, in turn, subjected to an in vitro cytotoxicity study against the human lung (A549) and breast (MCF-7) cancer cell lines as well as the human embryonic kidney (HEK293-T) cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The test compounds exhibited moderate cytotoxicity against the A549 cell line compared to staurosporine (IC50 = 0.22 ± 0.02 µM) and nitendanib (IC50 = 0.46 ± 0.06 µM) with IC50 values in the range 13.36 ± 0.29–52.16 ± 2.40 µM. Moderate cytotoxicity was also observed for the test compounds against the MCF-7 cell line compared to staurosporine (IC50 = 0.25 ± 0.02 µM) and nitendanib (IC50 = 0.44 ± 0.03 µM) with IC50 values in the range 11.98 ± 0.09–30.66 ± 1.15 µM. The potential of the test compounds to inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase activity was evaluated through enzymatic assay in vitro. Compounds 3f, 3i and 3k exhibited strong activity against this enzyme compared to the reference drugs, staurosporine (IC50 =5.18 ± 0.003 µM) and nintendanib (IC50 = 6.87 ± 0.002 µM), with IC50 values of 3.59 ± 0.02 µM, 3.76 ± 0.01 µM and 5.36 ± 0.02 µM, respectively. The results of VEGFR-2 inhibition correlated well with that of the cytotoxicity assay. The modelled structures show that the binding of the test compounds into the VEGFR-2 active site was driven mostly by hydrogen bonding and hydrophobic interactions.