Design, synthesis, and anticancer evaluation of spirooxindole-1,2,3-triazole hybrids as potent VEGFR-2 inhibitors

Hybrids of spirooxindole and 1,2,3-triazole have been the subject of extensive research because of their potential as multitarget anticancer pharmaceuticals. Potential novel anticancer treatments involving small-molecule kinase inhibitors are a constant focus of research. Spirooxindole-based compounds are considered a promising framework due to their notable ability to inhibit VEGFR-2. Considering studies showing that cancer chemotherapy can have long-lasting adverse effects on cognitive function and quality of life, a series of spirooxindole compounds has been designed and synthesized using a classical [3 + 2] cycloaddition reaction. Out of 29 compounds, nine compounds showed a significant cytotoxic effect against breast (IC₅₀ of 13.12 ± 0.38 and 12.65 ± 1.71, for compounds 4a and 7p, respectively), colon (IC₅₀ of 5.68 ± 0.44, 0.25 ± 0.17, 7.38 ± 2.1, 3.3 ± 1.25, 5.52 ± 0.55, and 6.19 ± 0.23, for compounds 4a, 4j, 7j, 7 k, 7p, and 7 t), liver (IC₅₀ of 6.1 ± 2.38, 6.82 ± 3.66, 16.86 ± 1.5, and 7.93 ± 1.515 for compounds 4e, 4i, 7j, and 7p, respectively), and lung cancer (IC₅₀ of 6.46 ± 2.65, 5.23 ± 3.91, 8.78 ± 0.39, and 9.58 ± 0.62, for compounds 4a, 7f, 7j, and 7p). After 48 h of treatment, the IC_50s of the tested compounds induced cell cycle arrest in the sub-G1 phase, accompanied by a significant decrease in the G0/G1, S, and G2/M phases. Compounds 7f, 7j, 7, and 4j exhibited potent VEGFR-2 inhibition with IC₅₀ values of 31.2 ± 1.4, 36.7 ± 1.7, 29.2 ± 0.9 nM compared to Sorafenib (IC₅₀ value of 32.1 nM). Molecular docking and experimental studies showed strong binding and inhibition of compounds 7f, 7j, 7t, and 4j to VEGFR-2. The results suggest that compounds 7f, 7j, 7t, and 4j are potential and effective anti-cancer agents targeting angiogenesis.