Identification of selective N-pyridinsulfonyl indole based thiosemicarbazone derivatives as potential antiproliferative agents against lung cancer cells.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide and necessitates the development of novel targeted agents. In this study, a series of new thiosemicarbazone derivatives (5a-r) were synthesized and evaluated for their anticancer potential through combined in vitro and in silico approaches. Cytotoxic activities were assessed against lung adenocarcinoma cells (A549) and normal bronchial epithelial cells (BEAS-2B). Among the tested compounds, 5p emerged as the most potent derivative, exhibiting an IC50 value of 3.41 µM against A549 cells, superior to sorafenib (IC50 = 4.02). Importantly, 5p demonstrated a remarkably high selectivity index (SI = 17.5), substantially exceeding that of sorafenib (SI = 5.5), indicating preferential cytotoxicity toward cancer cells. Apoptosis assays revealed that 5p significantly induced apoptotic cell death in A549 cells, supporting that its antiproliferative activity is mediated, at least in part, through apoptosis induction. Molecular docking and MM-GBSA binding free energy analyses against EGFR, VEGFR-1, and VEGFR-2 further supported the experimental findings. Compound 5p exhibited strong docking scores (-11.452, -13.864, and -11.487 kcal mol-1 for EGFR, VEGFR-1, and VEGFR-2, respectively) and the most favorable binding free energies (ΔG_bind = -91.95, -87.05, and -80.53 kcal mol-1), outperforming reference inhibitors gefitinib and sorafenib in several targets. Molecular dynamics simulations (250 ns) confirmed the stability of the 5p-kinase complexes based on RMSD analysis. In silico ADME analysis revealed that the synthesized compounds generally possess favorable drug-likeness. The combined in vitro cytotoxicity, high selectivity index, and strong in silico kinase binding profiles identify compound 5p as a promising lead candidate for further development in lung cancer therapy.