What question did this study set out to answer?

The study aims to synthesize isatin-amide derivatives and evaluate their anti-cancer potential, especially against VEGFR-2.

February 14, 2026Open Access

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

Key Points

The study aims to synthesize isatin-amide derivatives and evaluate their anti-cancer potential, especially against VEGFR-2.
Synthesis of isatin-amide derivatives through Ag(I)-NHC/TBHP-promoted oxidative amidation.
Evaluation of anti-proliferative activity on MCF-7 and HepG-2 cell lines.
Assessment of bioavailability via Caco2 cell membrane permeability studies.
Molecular docking studies using VEGFR-2 to analyze binding affinities.
Compound 5j showed superior anti-proliferative activity (IC50 < 2 µM) compared to Sunitinib (IC50 2.2-4.8 µM).
Compounds 5d and 5n exhibited IC50 values <4 µM against MCF-7, better than Sunitinib.
Compounds 5d (IC50 0.09 µM) and 5j (IC50 0.06 µM) showed enhanced VEGFR-2 inhibition compared to Sunitinib (IC50 0.14 µM).
In bioavailability studies, compound 5n demonstrated the highest intracellular concentration at sixth hour in Caco2 cells.
Molecular docking revealed compounds 5d, 5j, and 5q had favorable binding constants and energies compared to Sunitinib.

Abstract

ABSTRACT 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 IC 50 = <2 µM) displayed superior activity against MCF‐7 and HepG‐2 cell lines than the standard drug Sunitinib (IC 50 = 2.2–4.8 µM). Compounds 5d and 5n showed greater activity (IC 50 = <4 µM) against MCF‐7 than the positive control (IC 50 = 4.8 µM). In addition, compound 5d had a comparable activity (IC 50 = 2.5 µM) against HepG2 to the positive control (IC 50 = 2.2 µM). As well, compounds 5d (IC 50 = 0.09 µM) and 5j (IC 50 = 0.06 µM) were found to be 1.55‐ and 2.33‐fold, respectively, more active against VEGFR‐2 inhibition than Sunitinib (IC 50 = 0.14 µM). Compound 5n showed comparable (IC 50 = 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.

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

Key Points

Abstract

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