Exploring a novel thiazole derivatives hybrid with fluorinated-indenoquinoxaline as dual inhibitors targeting VEGFR2/AKT and apoptosis inducers against hepatocellular carcinoma with docking simulation

[Display omitted] •Designed and synthesized a new thiazole hybrid fluorinated indenoquinoxaline and confirmed the structure.•Investigated the anti-proliferative activity against HepG-2 and HuH-7 liver tumor cell lines.•Demonstrated potent inhibition of VEGFR2/AKT signaling pathways for most active derivative.•The promising hybrid compound induced apoptosis in hepatocellular carcinoma cells at the G2/M phase.•In-silico docking simulation was performed to determine the binding affinity and interaction mechanisms with VEGFR2/AKT. Hepatocellular carcinoma (HCC) ranks as the third most prevalent reason for cancer-related death on a global scale. Tyrosine kinase inhibitors (TKIs) continue to be the primary treatment option for advanced hepatocellular carcinoma. A series of fluoro-11H-indeno[1,2-b]quinoxaline derivatives as an HCC drug targeting the VEGFR2/AKT axis was designed and synthesized. The novel compounds were investigated against HepG-2 and HuH-7 liver tumor cell lines. Compound 5 was the most active derivative against HepG-2 and HuH-7 cell lines with IC50 = 0.75 ± 0.04 and 3.43 ± 0.16 μM, respectively, in contrast to Sorafenib which shows IC50 values of 5.23 ± 0.31 and 4.58 ± 0.21 μM, respectively. IC50 values on normal liver cells (THLE-2) show that all tests are more selective than Sorafenib, prompting further research. The most promising cytotoxic compound has virtually equal VEGFR2 inhibition efficacy to Sorafenib. The total VEGFR2 and p-VEGFR2 inhibitory effects were subsequently evaluated, showing 38.32 % and 77.64 % attenuation, respectively. Compound 5 also reduced total and phosphorylated AKT concentrations in HepG-2 cells by 55.29 % and 78.01 %, respectively. Furthermore, Compound 5 upregulated BAX and caspase-3 and downregulated Bcl-2 to promote apoptosis. Hybrid 5 stops HepG-2′s cell cycle at the S phase 48.02 % higher than untreated. Docking experiments assessed AKT and VEGFR2 binding patterns.