Synthesis, crystal structure, cytotoxicity (MCF-7 and HeLa) and free radical scavenging activity of the hydrazones derived from 2-methylsulfonyl-5-nitrobenzaldehyde

Abstract

• The geometry of hydrazones of 2-methylsulfonyl-5-nitrobezaldehyde was determined. • Hydrazone 3b exhibited increased cytotoxicity against the MCF-7 and HeLa cell lines. • Increased hydrophobic interactions are predicted with VEGFR-2. • The test compounds have potential to inhibit VEGFR-2 tyrosine kinase phosphorylation. • Their DPPH free radical scavenging potential was determined in vitro and in silico. The rising levels of breast and cervical cancers among women have become public health problem with high economic burden globally and more especially in low- and middle-income countries. This necessitates discoving new and potent anticancer drugs with reduced or no side effects. The hydrazones derived from 2-formyl-4-nitrophenyl methanesulfonate were characterized using a combination of spectroscopic and single-crystal X-ray diffraction (XRD) techniques. The compounds were, in turn, evaluated for antigrowth effect in vitro against the human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cell lines and for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The presence of a chlorine atom on the para position of the phenylhydrazone moiety of 3b resulted in increased cytotoxicity against the MCF-7 and the HeLa cell lines compared to camptothecin (IC 50 = 9.15 ± 0.84 µM and 3.71 ± 0.16 µM, respectively) with IC 50 values of 5.64 ± 0.84 µM and 2.40 ± 0.13 µM, respectively. Compounds 2 , 3a and 3b were found to exhibit significantly reduced toxicity against the Vero cells compared to the anti-cancer drugs, doxorubicin (IC 50 = 0.78 ± 0.04 µM) and nintedanib (IC 50 = 0.24 ± 0.02 µM) with the IC 50 values of 17.86 ± 1.12, 11.89 ± 1.01 and 24.42 ± 0.70 µM, respectively. The hydrazones 3a and 3b exhibited a strong inhibitory effect against the vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase (IC 50 = 5.78 ± 0.039 μM and 5.79 ± 0.053 µM, respectively) compared to the carbaldehyde precursor 2 (IC 50 = 8.01 ± 0.052 µM) though less active compared to nintedanib (IC 50 = 1.05 ± 0.193 µM). The hydrazone derivatives exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity compared to ascorbic acid and the parent 2-formyl-4-nitrophenylmethanesulfonate. In silico molecular docking studies revealed the binding potential of the hydrazones at the active site of VEGFR-2 tyrosine kinase and cytochrome c peroxidase.