Evaluation of quinoxaline-2-one-hydrazone hybrid as VEGFR-2 inhibitors and apoptosis inducers: Design, synthesis, anticancer assessment, and in silico study
Journal of Molecular Structure, cilt.1378, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1378
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.molstruc.2026.147239
- Dergi Adı: Journal of Molecular Structure
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Anahtar Kelimeler: Anticancer, Apoptosis, In silicostudy, Quinoxalin-2-one, VEGFR-2
- Erciyes Üniversitesi Adresli: Evet
Özet
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis and cancer progression, attracting attention as a significant target for anticancer drug development. In this study, a new series of quinoxaline-2-one–based molecules was designed, synthesized, and evaluated for anticancer activity as VEGFR-2 inhibitors. The antiproliferative assessment against HepG2 and MCF-7 cancer cell lines identified compounds 11a, 11d, 11e, and 11g as promising cytotoxic derivatives. Particularly 11g, which demonstrated IC50 values of 3.95 and 7.51 µg/mL, in comparison to sorafenib with IC50 values of 7.72 and 12.91 µg/mL against the two cell lines, respectively. Additionally, compound 11g displayed considerable VEGFR-2 inhibition, with an IC50 of 0.172 µg/mL, compared with sorafenib (IC50 = 0.078 µg/mL). Moreover, 11g showed selectivity indices of approximately 4.8 and 2.5 to HepG2 and MCF-7, respectively. Furthermore, 11g caused a cell cycle block at the G0-G1 phase in HepG2 cells, resulting in a 1.6-fold increase in cell population and a 12-fold increase in apoptosis rate compared to HepG2 control cells. In the meantime, 11g dramatically raised the BAX/Bcl-2 ratio to about 18 times. It also increased caspase-3 (6.9-fold) and caspase-9 (10-fold) and inhibited proinflammatory cytokine TNF-α and IL-6R by 1.14-fold and 2.4-fold, respectively. Molecular docking and dynamic simulation of compound 11g showed favorable binding interactions and high stability within the VEGFR-2 active site. Although ADME predictions suggested advantageous drug-like physicochemical profiling, the pharmacokinetic characteristics, including solubility /permeability and toxicity concerns, represent the primary developability constraints. Collectively, the promising biological results highlight quinoxaline-2-one as a promising scaffold for developing novel VEGFR-2-targeted anticancer agents and identify 11g as a lead compound for further structural optimization.