Nishith Teraiya

The present work deals with design, synthesis, cytotoxic evaluation and in-silico GSK-3β inhibitory study of 1,2,3-triazole-linked indirubin derivatives. The synthesized compounds were screened for in-vitro cytotoxicity against a panel of adherent (Capan-1, HCT-116, LN229 and NCI-H460) and suspension cell lines (Molt-4, HL-60, K562 and Z138). Most of the derivatives showed weak to moderate cytotoxicity (CC50 > 50 µM). Among study, compound AM-20 showed highest cytotoxicity against glioblastoma LN229 cells with CC50 of 4.78 ± 0.056 µM and moderate against HCT-116 cells (CC50 = 28.41 ± 1.16 µM). Also, AM-1 and AM-14 exhibited moderate cytotoxicity against LN229 with CC50s of 34.19 and 40.87 µM, respectively. Importantly, all molecules showed higher cytotoxicity against cancer cells than normal HEL299 and PBMC cells, indicating selectivity against cancer. Further, SAR investigation found that moderately electron-donating group such as, methoxy and electron-withdrawing (nitro) was favourable for higher cytotoxicity. Besides, molecular docking against GSK-3β revealed that AM-20, AM1 and AM-14 showed the highest dock scores (-11.7 kcal/mol, -9.9 kcal/mol, -9.3 kcal/mol) than bioacetoxime (-9.2 kcal/mol). Molecular dynamics simulation for 100 ns confirmed the stability of the protein-ligand complexes with favorable RMSD, and RMSF and persistent hydrogen bond interactions with key active site residues. Overall, the study identifies triazole-linked indirubin derivatives, particularly AM-20, AM-1 and AM-14, as promising lead molecules for further optimization towards glioblastoma-targeted anticancer therapy.

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.

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.

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.

The present study described the synthesis and anticancer activity of new indole–piperidine hybrids functionalized with piperidin‐4‐yl‐benzamide ( 9a–n ) and piperidin‐4‐yl‐urea ( 11a–g , 13a–f ) moieties. All the newly synthesized compounds were purified by reverse phase flash chromatography and characterized by FTIR, ¹ H and ¹³ C NMR, LC–MS, and elemental analysis. Their in vitro anticancer activity was tested against the NCI‐60 human tumor cell lines (National Cancer Institute, USA). The results revealed that compounds 9c , 11d , 13b , and 13e were found active against UO‐31 (renal cancer) having growth (%) as −22.98%, −49.98%, −83.76%, and −82.75%, respectively. While compound 11f exhibited notable activity against RPMI‐8226 (leukemia) and MDA‐MB‐468 (breast cancer). Moreover, in silico docking studies revealed effective VEGFR‐2 binding with the receptor and formed stable protein–ligand complex with low docking scores. Additionally, drug‐likeness and ADMET predictions indicated favorable pharmacokinetic profiles with no associated toxicity concerns.