Ag(I)-NHC/TBHP promoted aqueous synthesis of some new quinoline-aromatic amides; Anti-proliferative, Anti-VEGFR-2 and Molecular docking studies

Herein, we synthesized some new quinoline-aromatic amides (5a-5o) as VEGFR-2 targeting anti-proliferative agents via Ag(I)-NHC/TBHP promoted oxidative amidation of 4-(((quinolin-4-ylmethylene)amino)methyl)benzaldehyde (3) with several anilines (4a-4o) in benign water solvent. The anti-proliferative activity of derivatives (5a-5o) over two human cancer cell lines such as HepG-2 and MCF-7 revealed that majority of derivatives had selectively better activity against HepG2. In specific, compound 5o displayed higher activity against two cells than the Sorafenib with IC50 values <3 mu M. Also, compound 5g showed almost similar activity (IC50; 2.5-4.2 mu M) against two cell lines with the positive control (IC50; 2.2-3.4 mu M). Active compounds 5d-5g 5i-5j, 5l and 5o found in anti-proliferative activity were then evaluated for their VEGFR-2 inhibitory activities and observed that compound 5o showed higher inhibition (IC50 = 33.5 nM) than the Sorafenib (IC50 = 35.6 nM), while, compound 5g had comparable inhibition (IC50 = 36.1 nM) with the positive control. In silico molecular docking studies revealed the important binding interactions of compounds 5e, 5g, 5l, 5o and Sorafenib with VEGFR-2 (pdb id 3VHE) and compounds 5e, 5g, 5l and 5o displayed encouraging binding energies and inhibition constants than the Sorafenib. Finally, the results of in silico SWISSADME showed that compounds 5e, 5g, 5l and 5o followed Lipinski, Ghose, Veber, Egan and Muegge rules without any deviation and showed high gastrointestinal (GI) absorption.