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.

Glycogen synthase kinase-3 beta (GSK-3β) is a multifunctional serine/threonine kinase mediating multiple cellular functions, such as differentiation, apoptosis, and cell proliferation. Because of their ability to alter carcinogenic pathways, GSK-3β inhibitors are being explored for the development of anticancer molecules. In the present study, we synthesized and evaluated the cytotoxic properties of a series of twenty indole–triazole-linked pyrazolone derivatives, 10Aa–Ed. All derivatives were characterized by FTIR, ¹H/¹³C NMR, and high-resolution mass spectrometry (HRMS) methods. All compounds and standards, sunitinib and 5-Fluorouracil (5-FU), were screened against four adherent cell lines, including pancreatic adenocarcinoma (Capan-1), colorectal carcinoma (HCT-116), glioblastoma(LN229), and lung carcinoma (NCI-4460), and four non-adherent cell lines, including acute myeloid leukemia (HL-60), chronic myeloid leukemia (K562), T lymphoblast (MOLT4), and non-Hodgkin lymphoma (Z138). Among the screened derivatives, molecule 10Aa showed cytotoxicity against MOLT 4, Z138, and HL60 with CC₅₀ values of 14.45 μM, 15.34 μM, and 17.56 μM, respectively. GSK-3β kinase inhibition was evaluated with the 10Aa, which is capable of inhibiting GSK-3β in a dose-dependent manner. Additionally, molecular docking was performed to estimate the correlation between invitro data and GSK-3β binding affinity. The outcomes of the invitro experiments demonstrated strong concordance with the insilico data. The discovery yielded compounds 10Aa and 10Cd, which can be modified to create effective anticancer agents that target GSK-3β.

A series of 1,2,3-triazole-linked-thiazolidine-2,4-dione hybrids (SDP1–SDP15) were designed, synthesized, and evaluated for their antidiabetic potential. All structures were characterized by FT-IR and NMR spectroscopy (¹H and ¹³C). All derivatives exhibited significant in vitro inhibition of α-glucosidase (IC₅₀: 24.17–46.41 µg/mL) and α-amylase (23.25–50.66 µg/mL), comparable to the standard drug acarbose (IC₅₀: 25.18 and 32.53 µg/mL) and superior to the reference drug pioglitazone (IC₅₀: 84.24 and 79.74 µg/mL) for α-glucosidase and α-amylase, respectively. Molecule SDP8 emerged as the most potent with an IC50 of 24.17 and 23.25 µg/mL for α-glucosidase and α-amylase, respectively. Further, SDP8 exhibited a higher docking score of −10.7 kcal/mol and −10.4 kcal/mol against α-glucosidase and α-amylase than pioglitazone (−8.1 kcal/mol and −7.7 kcal/mol, respectively), suggesting that interaction with these two enzymes may be the cause for its antidiabetic activity. Furthermore, DFT analysis revealed favorable electronic properties with a low HOMO-LUMO energy gap, whereas ADMET predictions revealed moderate drug-like characteristics with some limitations, such as poor solubility, relatively high lipophilicity, and partial noncompliance with drug-likeness regulations. Overall, these results highlight triazole-linked thiazolidinedione hybrids as promising candidates for further development in T2DM, with SDP8 serving as a preliminary lead requiring additional optimization and validation.