Design, Molecular Docking, Synthesis, and Pharmacological Evaluation of Nabumetone-Derived Oxadiazole and Thiadiazole Schiff Bases as Potential EGFR Inhibitors for NSCLC

Lung cancer is the leading cause of cancer-related mortality globally, with non-small cell lung cancer (NSCLC) making up about 85%​. Overexpression or mutation of the epidermal growth factor receptor (EGFR) drives tumor proliferation in NSCLC. Although first-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib showing a rapid acquired resistance, often via the T790M mutation, limits their long-term effectiveness. This study synthesized two new nabumetone-based Schiff base derivatives with either a 1,3,4-oxadiazole ring (compounds 5a-c) or a 1,3,4-thiadiazole ring (compounds 6a-e). Characterization was conducted via FT-IR and NMR spectroscopy, and In vitro cytotoxicity assays using the MTT method were conducted on A549 non-small cell lung cancer (NSCLC) cells at different time intervals (e.g., 24 and 48 hours) to evaluate the antiproliferative effect. The 1,3,4-thiadiazole series (6a-e) was more potent than the oxadiazoles (5a-c), with compounds 6b and 6e showing the lowest 48-hour IC50 values (~40.9 µM and ~30.2 µM, respectively), outperforming erlotinib (IC50 ~51.3 µM)​. These results suggest that thiadiazole sulfur substituents (e.g., 6b, 6e) enhance anticancer activity through stronger interactions​​. This work introduces new nabumetone-derived compounds with promising antiproliferative activity against NSCLC, identifying compounds 6b and 6e as potent lead candidates for further in vivo and pharmacokinetic evaluation to advance EGFR-targeted cancer therapies​. Molecular docking investigations further validated these results, demonstrating that all compounds have stronger interactions within the EGFR binding pocket, achieving superior PLP fitness scores range from 90.61 to 78.46 compared to erlotinib 77.62. These computational findings support the experimental data, indicating the promising potential of these derivatives as EGFR inhibitors.