Design and synthesis of antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with potential VEGFR-2 inhibitory properties

  • Sci Rep. 2025 Jan 3;15(1):618. doi: 10.1038/s41598-024-82005-6.
Dalia R Aboshouk  1 ,  M Adel Youssef  2 ,  Siva S Panda  3 ,  Benson M Kariuki  4 ,  Mohamed S Bekheit  1 ,  Ahmed R Hamed  5 ,  Walid Fayad  6 ,  Ahmed A F Soliman  6 ,  Adel S Girgis  7
Affiliations
  • 1. Department of Pesticide Chemistry, National Research Centre, Dokki, 12622, Giza, Egypt.
  • 2. Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt.
  • 3. Department of Chemistry and Biochemistry & Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.
  • 4. School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, UK.
  • 5. Chemistry of Medicinal Plants Department, National Research Centre, Dokki, 12622, Giza, Egypt.
  • 6. Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt.
  • 7. Department of Pesticide Chemistry, National Research Centre, Dokki, 12622, Giza, Egypt. [email protected].
PMID: 39753596 DOI: 10.1038/s41598-024-82005-6
Abstract

Targeted therapy is preferable over Other therapeutics due to its limitation of drawbacks and better pharmaceutical outcomes. VEGF and its receptors have been observed to be hyper-activated in many Cancer types and are considered promising targets for assigning Anticancer agents. The current study is directed towards synthesis of novel antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with VEGFR-2 properties. The targeted agents were obtained through a two-step reaction. Addition of the appropriate 1-(acetylphenyl)-3-phenylurea 9a,b to the corresponding isatin 10a-f in ethanol containing a quantitative amount of Et2NH followed by acidic dehydration (AcOH/HCl) afforded the targeted agents 12a-j. Promising antiproliferation properties (MTT assay) were observed for most of the synthesized agents against HCT116 (colon), MCF7 (breast) and PaCa2 (pancreatic) Cancer cell lines relative to sunitinib. VEGFR-2 inhibitory properties are consistent with the antiproliferation properties exhibited against the tested cell lines. Compound 12b (R = 4-NHCONHPh, R' = H; % inhibition = 87.2) is the most promising/potent anti-VEGFR-2 agent synthesized with activity close to that of sunitinib (% inhibition = 89.4) at 10 μM. Molecular docking studies (PDB: 3WZE and 3AGD) support the antiproliferation effects against Cancer cell lines tested with VEGFR-2 inhibitory properties. The results are consistent with collaboration of the pharmacophores considered (2-oxoindolyl heterocycle and urea) in improving the bio-properties.

Keywords
2-Oxoindolin-3-ylidenes; Cancer; Molecular modeling; VEGFR-2.
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