Development and Biological Assessment of Thiazole-Based Pyridines for Targeted Therapy in Lung Cancer

The study aims to synthesize, characterize, and evaluate a series of novel compounds for their potential anticancer activity targeting the A549 lung cancer cell line. The hydrazonothiazole-based pyridine compounds (2a-2o) were characterized through melting point analysis, ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). Their physicochemical properties were evaluated using in silico tools, and all compounds were found to comply with Lipinski's drug-likeness rule, suggesting favorable drug-like characteristics. Biological activity studies revealed that all synthesized compounds exhibited potent cytotoxicity against the A549 cell line, with several compounds showing greater efficacy than the standard drug, cisplatin. Selectivity indices were also calculated, revealing that compounds 2b, 2c, 2f, and 2m exhibited enhanced selectivity for cancer cells relative to healthy cells. Mechanistic studies using flow cytometry demonstrated that these compounds induced apoptosis, with compound 2m demonstrating the highest apoptotic activity. Mitochondrial membrane potential assay and caspase-3 activation confirmed the involvement of mitochondrial pathways in apoptosis induction. Furthermore, MMP-9 enzyme inhibition assays identified compound 2f as the most effective inhibitor, with molecular docking and dynamics simulation studies confirming its strong binding interactions with key residues in the enzyme's active site. Overall, this study suggests that the synthesized compounds, particularly 2b, 2c, 2f, and 2m, hold promise as potential anticancer agents for further development and optimization in the treatment of lung cancer.