Benzylpyrazolyl naphthoquinones as potential VEGFR-2, GPCR and PPAR inhibitors: Synthesis, anti-cancer evaluation, molecular docking and DFT studies

The present study reports the synthesis of benzylpyrazolyl naphthoquinones using nano-Fe3O4 supported Bronsted acidic ionic liquid ([nano-Fe3O4@BenzImi]SO3H) as magnetically retrievable solid acid catalyst. In vitro anti-cancer activity of the synthesized benzylpyrazolyl naphthoquinones have been evaluated against breast cancer cell line (MCF-7) and liver cancer cell line (HepG2). Compound 4h was found to be the most active compounds with IC50 values 0.0436 +/- 0.31 mu M against MCF 7 cell line whereas compound 4e was displayed highest activity with IC50 values 0.0314 +/- 0.16 mu M against HepG2 cell line as compared to the standard 5-fluorouracil (0.0384 +/- 0.10 and 0.0330 +/- 0.09 mu M). Furthermore, in silico bioactivity studies revealed that the compounds have significant interactions with the drug targets. The molecular docking studies revealed that the compounds have significant binding affinity with potential receptors such as vascular endothelial growth factor receptor (VEGFR-2), G-protein coupled receptor (GPCR) and peroxisome proliferator-activated receptors (PPAR). The compound 4g has strong hydrogen bond interaction with VEGFR-2 as well as the lowest binding energy (-9.3 kcal/mol-1), similarly, 4c has strong hydrogen bond interaction with in GPCR as well as the lowest binding energy (-7.8 kcal/mol-1) whereas 4a and 4e show strong hydrogen bond interaction with in PPAR as well as lowest binding energy (-10.1 kcal/mol- 1 and -10.1 kcal/mol- 1) as compared to other compounds. The docking studies revealed that these compounds gets stabilized via hydrogen bonding interactions, van der Waals contacts and electrostatic interactions which were further supported through estimation of HOMO-LUMO energies, ionization potential, electron affinities, dipole moment etc. using density functional theory (DFT) analysis. The work highlights biological significance of benzylpyrazolyl naphthoquinones as a potential anti-cancer reagent.