Synthesis, Nanoformulation, Molecular Modeling, and Anticancer Studies of 1,2,3-Triazole/Oxo-2-Thioxo-Thiazolidine Hybrids Using NF-κB and p-AMPK Pathways

This study reports the synthesis of triazole-rhodanine hybrid compounds (4a-c) via copper-catalyzed click chemistry as multi-target anticancer agents for non-small-cell lung cancer (NSCLC), achieving yields of 78–92%. Comprehensive structural characterization was accomplished through spectroscopic analysis (FT-IR,1H NMR,1³C NMR, elemental analysis, and HRMS). The synthesized derivatives demonstrated significant anticancer activity with IC50 values ranging from 47.71–70.10 μM against A549 cells and selectivity indices (SI) of 1.28–3.56. Molecular docking simulations revealed strong binding affinities (ΔG = −8.41 to −10.42 kcal/mol) against critical oncogenic targets: nuclear factor kappa B (NF-κB), Cyclin D1, phosphorylated AMP-activated protein kinase (p-AMPK), and vascular endothelial growth factor 1 (VEGF1), establishing a multi-target therapeutic mechanism. Chitosan-based nanoformulations substantially enhanced therapeutic efficacy by 2.5–4.2-fold, with nanoparticles (size: 59.2–85.2 nm, PDI: 0.807–1.00) achieving IC50 values of 37.58–46.02 μM. The N-4b nanoformulation exhibited the highest therapeutic potential (IC50 = 37.58 μM) with excellent drug-likeness properties and superior selectivity (SI = 4.32). This integrated synthetic and computational approach provides a novel framework for developing multi-target triazole-rhodanine hybrids as promising NSCLC therapeutics.