ImesAgCl/TBHP Promoted Aqueous Synthesis of Isatin‐Amide Derivatives: Anti‐proliferative, Anti‐Vascular Endothelial Growth Factor Receptor 2, Bioavailability and Molecular Docking Studies

Cancer is a worldwide health burden that influences about every geographic location and socioeconomic class. One of the main challenges that remains is the appearance of resistance to cancer therapy. It is found that vascular endothelial growth factor receptor 2 (VEGFR-2) is overexpressed in a number of tumours. Few FDA approved drugs (such as Sorafenib, Sunitinib, Nintedanib and Cabotanzinib), which target VEGFRs, however, a significant issue with the monotherapy of these agents is drug resistance. Hence, in the present work. Some isatin-aromatic amides (5a-q) were synthesised via Ag(I)-NHC/TBHP-promoted tandem one-pot oxidative amidation between 3-((3-hydroxypropyl)imino)-1-methylindolin-2-one (3) and anilines (4a-q) in water as a key approach. The anti-proliferative activity of amides (5a-q) revealed that compound 5j (50% inhibitory concentration [IC₅₀] = <2 µM) displayed superior activity against MCF-7 and HepG-2 cell lines than the standard drug Sunitinib (IC₅₀ = 2.2-4.8 µM). Compounds 5d and 5n showed greater activity (IC₅₀ = <4 µM) against MCF-7 than the positive control (IC₅₀ = 4.8 µM). In addition, compound 5d had a comparable activity (IC₅₀ = 2.5 µM) against HepG2 to the positive control (IC₅₀ = 2.2 µM). As well, compounds 5d (IC₅₀ = 0.09 µM) and 5j (IC₅₀ = 0.06 µM) were found to be 1.55- and 2.33-fold, respectively, more active against VEGFR-2 inhibition than Sunitinib (IC₅₀ = 0.14 µM). Compound 5n showed comparable (IC₅₀ = 0.16 µM) VEGFR-2 inhibition to Sunitinib. Furthermore, in vitro bioavailability studies showed that compound 5n crossed the Caco2 cell membrane and showed the highest intracellular concentration after sixth hour incubation, in comparison to compounds 5d, 5j and Sunitinib. Finally, in silico molecular docking studies on VEGFR-2 (PDB ID 3VHE) revealed that compounds 5d, 5j, and 5q showed encouraging inhibition constants (68.5-154.92 nM) and binding energies (-9.29 to -9.77 kcal/mol) compared to Sunitinib (inhibition constant = 248.72 nM) and binding energy = -9.01 kcal/mol). Specifically, compounds 5d and 5j established an H-bond with the ASP1046 residue, similar to the standard drug Sunitinib.