Novel Nabumetone-Chalcone-Based Pyridine Hybrids: Synthesis, Characterization, and Cytotoxic Activity against the A549 Lung Cancer Cell Line and Normal Human Dermal Fibroblasts (HDFn)

Abstract

Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality, necessitating the continuous discovery of targeted therapies. Aim of the Study: This study aimed to synthesize and characterize six novel nabumetone-derived heterocyclic compounds (4-9) by integrating chalcone derivatives with pyridine-derived scaffolds and evaluate their cytotoxic activity. Materials and Methods: The structures of these compounds were validated by Infrared Spectroscopy, Proton Nuclear Magnetic Resonance (1H-NMR), and Carbon Nuclear Magnetic Resonance (13C-NMR) Spectroscopy. All substances were evaluated for their capacity to inhibit cancer cells via the MTT assay in the A549 lung cancer cell line and normal human dermal fibroblasts (HDFn). We established the IC50 values for all drugs using a 48-hour incubation period. Results: The para-pyridone compound )6 (had the highest cytotoxicity against cancer cells (31.82 µg/mL), whereas the meta-pyridine compound (8) also showed significant cytotoxicity (38.09 µg/mL). Compound (6) exhibited biological activity that surpassed that of the reference medication, Erlotinib, a contemporary chemotherapeutic agent (34.10 µg/mL). Furthermore, both compounds (6) and (8) had considerable Selectivity Indices (SI: 4.92 and 3.90, respectively). Discussion: Our research demonstrates that both the fundamental architecture of each chemical and the locations of its functional groups are crucial in influencing its biological activity. Conclusion: These findings suggest that both substituted pyridone cores and substituted 2-aminopyridine cores may serve as promising scaffolds for further optimization and biological evaluation.