Design, synthesis and anticancer evaluation of novel hydrazide-2-oxindole analogues as GSK-3β kinase inhibitors

Abstract

GSK-3β plays an essential role in cancer progression, making it a promising target for therapeutic intervention with glycogen synthase kinase (GSK-3β) inhibitors. The designed compounds were discovered for their potential role against the proliferation of cancer via targeting GSK-3β. In the present study, hydrazide-2-oxindole analogues were designed, synthesised, and evaluated for anticancer efficacy against GSK-3β. Compounds were screened against Capan-1, HCT-116, LN-229, MCI-4460, DND-41, HL-60, K-562, MOLT4, Z-138 cells and normal cell line HEK 293. Among the compounds, 6Eb and 6Ec showed the highest selective cytotoxicity against prostate cancer (Capan-1) with CC₅₀ values of 9.40 μM, and 8.25 μM, respectively. Furthermore, the mechanism of the anticancer effect was evidenced by 6Eb and 6Ec against GSK-3β kinase with IC_50s of 11.02 μM and 59.81 μM, respectively. In addition, elevation of β-catenin and downregulation of NF-kB and STAT3 in the western blot by 6Eb evidenced inhibition of GSK-3β kinase as the cause of cytotoxicity. Furthermore, in vitro results were supported by docking scores of −10.5 kcal mol⁻¹ and −8.8 kcal mol⁻¹, respectively, as compared to bio-acetoxime (−7.7 kcal mol⁻¹). Furthermore, the higher stability in molecular dynamics simulations validated the docking approach and indicated anti-cancer effects by inhibiting GSK-3β. In addition, the density functional theory analysis identified electronic distribution in compounds, which was correlated to the findings of docking and molecular dynamic simulation on their participation in polar and lipophilic interactions with kinase. Moreover, the compounds meet the drug-likeness criteria, suggesting they could be candidates for the development of drugs against cancer that target GSK-3β.