Research Article

Design, Synthesis and In Silico Evaluation of Benzotriazole-Based Urea Derivatives as Potential VEGFR-2 Inhibitors

Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in the process of tumor angiogenesis and is a validated target for therapeutic intervention in cancer. Here, in this study reported the design, synthesis, and evaluation of a new series of benzotriazole based urea derivatives (bc1–bc5) as potential VEGFR-2 inhibitors. The synthetic approach involved the N1-acylation of benzotriazole, followed by hydrazide formation and further reactions with a variety of substituted aromatic isocyanates to yield target compounds in good yields (69–78%). The structures of the synthesized derivatives were confirmed by FTIR, ¹H NMR, ¹³C NMR, mass spectrometry, and elemental analysis. Molecular docking studies were performed against the VEGFR-2 kinase domain (PDB ID: 4ASD), using Sorafenib as the reference inhibitor. All compounds exhibited favorable binding affinities (−8.77 to −9.37 kcal/mol), with bc2 showing the highest docking score for the synthesized derivatives. The binding interactions showed critical hydrogen bonds with residues like CYS919 and ASP1046, along with a significant hydrophobic component and π–π interactions in the ATP-binding pocket. SAR analysis underlined the importance of the benzotriazole–urea scaffold and indicated that electronwithdrawing groups, especially CF₃, increased binding affinity. ADMET predictions showed good oral absorption, moderate distribution, acceptable physicochemical properties, and adherence to Lipinski’s rule of five. However, CYP inhibition, hepatotoxicity, AMES positivity predicted that biological and toxicity evaluation should be carried out. Overall, this study demonstrates that the synthesized benzotriazole-based urea derivatives could represent useful lead candidates for continued development as anti-cancer agents targeting VEGFR-2.