Design, Synthesis, and Biological Evaluation of Isatin-Based 3-Phenoxybenzoic Acid Derivatives as VEGFR-2 Inhibitors with Anti-Angiogenic Potential

Abstract

Objectives: Due to its significant role in supporting the development and spread of cancer, the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2) of angiogenesis has been used in cancer treatment. The research presented created and synthesized a number of phenoxy benzoic acid derivatives. This work develops and evaluates four novel drugs targeting cancer and the VEGFR.

Methods: For the chemical synthesis, we used phenoxy benzoic acid, sulphuric acid, methanol, hydrazine hydrate, Isatin derivatives, and glacial acetic acid.

Results: In vitro cell line investigations and silico docking studies showed antitumor efficacy for the produced substances. The results demonstrated that the inclusion of isatin in the molecular framework enhanced receptor binding by interacting with critical amino acids essential for VEGFR-2 enzymatic activity. The docking study showed that compounds F1 and F4 had the highest binding affinities, with S-scores of -8.54 and -8.2, respectively, interacting with key amino acids such as Glu885, Cys1045, and Asp1046. The in vitro cytotoxicity results demonstrated selective anticancer activity. Compound F4 exhibited the highest potency against MCF-7 cells (IC50 = 5.76 µM), while F1 displayed notable activity against HepG2 cells (IC50 = 9.73 µM). Compared to sorafenib, the synthesized compounds showed selective cytotoxicity toward cancer cells while sparing normal cells. These findings suggest that the newly synthesized compounds could be potential VEGFR-2 inhibitors with selective anticancer properties.

Conclusion: The synthesized Isatin-based 3-phenoxybenzoic acid derivatives exhibited strong VEGFR-2 inhibitory activity and selective cytotoxicity against cancer cells while reducing toxicity to normal cells.