VEGFR‐2 Targeting Oxadiazole‐Pyrazole Hybrids: Synthesis, Molecular Docking, and Cytotoxic Evaluation in Cancer Cells

The development of novel VEGFR‐2‐targeted anticancer agents remains essential due to the limitations of currently available therapies, including toxicity, resistance, and insufficient selectivity. In this study, a series of 20 oxadiazole‐pyrazole hybrid derivatives ( BNK‐1‐20 ) were rationally designed and synthesized based on key pharmacophoric features of VEGFR‐2 inhibitors. The compounds were evaluated for their antiproliferative activity using the MTT assay in A549 (lung), HepG2 (hepatocellular), and MDA‐MB‐231 (breast) cancer cell lines, along with CCD‐34Lu normal fibroblasts to assess selectivity. The results revealed a clear cell‐type‐dependent response, with HepG2 cells showing the highest sensitivity, followed by A549, while minimal activity was observed in MDA‐MB‐231 cells. Among the synthesized compounds, BNK‐3 , BNK‐6 , BNK‐7 , and BNK‐8 demonstrated the most favorable balance between cytotoxic activity and selectivity, particularly in HepG2 cells. Further investigation of VEGFR‐2 protein levels revealed a compound‐dependent modulation pattern, in which selected derivatives reduced VEGFR‐2 expression, whereas others induced compensatory upregulation. Molecular docking studies supported these findings, showing that compounds with strong VEGFR‐2 suppression exhibited favorable binding interactions within the ATP‐binding pocket. Overall, these results highlight the potential of oxadiazole‐pyrazole hybrids as promising scaffolds for the development of selective VEGFR‐2‐targeted anticancer agents.