New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study

Drug Dev Res. 2024 Jun;85(4):e22218. doi: 10.1002/ddr.22218.

Abstract

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).

Keywords: MTT; VEGFR‐2; benzimidazole; cytotoxicity; molecular docking; oxadiazole.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Benzimidazoles* / chemical synthesis
  • Benzimidazoles* / chemistry
  • Benzimidazoles* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Docking Simulation*
  • Oxadiazoles* / chemical synthesis
  • Oxadiazoles* / chemistry
  • Oxadiazoles* / pharmacology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2* / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2* / metabolism

Substances

  • Vascular Endothelial Growth Factor Receptor-2
  • Oxadiazoles
  • Antineoplastic Agents
  • Benzimidazoles
  • KDR protein, human
  • Protein Kinase Inhibitors
  • Vascular Endothelial Growth Factor A

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