Design, Synthesis, and In Silico Evaluation of Novel Benzimidazole-Based Urea Derivatives Targeting VEGFR-2

Abstract

regulated primarily via vascular endothelial growth factor receptor-2 (VEGFR-2). Although VEGFR-2 is a confirmed target in anti-tumor management, available inhibitors currently suffer from many limitations such as drug resistance and dose-related toxicity, so it becomes necessary to develop novel and more safe inhibitors. The aim of this study is to design, synthesize, and evaluate a new series of benzimidazole-urea derivatives (U1–U4) as potential inhibitors of VEGFR-2 with enhanced binding affinity and better drug-likeliness properties. Methods: Four compounds benzimidazole-urea derivatives were synthesized chemically and analyzed structurally using FT-IR, 1H-NMR, and 13C-NMR spectroscopy. Molecular docking studies were performed against VEGFR-2 (PDB ID: 4ASD) to detect interaction profiles especially binding affinity, with Sorafenib which is used as a reference inhibitor. Physico-chemical properties and pharmacokinetics (ADME) properties were predicted to evaluate drug-likeness and oral bioavailability. Statistical analysis used. Docking scores and binding energies were obtained from molecular docking simulations and analyzed in comparison with the reference drug; no experimental statistical tests were applied. Results: The four synthesized derivatives exhibited high binding affinities toward VEGFR-2. The best among them were compound U4 which showed the highest docking score (−9.8877 kcal/mol), better than that of Sorafenib (−9.3847 kcal/mol). We identified the key interactions with critical amino acid residues, including Glu885, Asp1046, and Cys919, which indicating stable binding within the ATP-binding pocket. More interesting result were in silico ADME analysis that revealed beneficial physicochemical properties and expected oral bioavailability for all the four synthesized compounds. Conclusion: The newly synthesized benzimidazole-urea derivatives exhibit potential VEGFR-2 inhibitory activity, favourable binding properties and drug likeliness. These compounds are promising and could be more extensively tested in biological systems as anti-angiogenic and anticancer drugs.