Diaryl Ether Derivatives as Dual Inhibitors of Selective COX-2 and EGFR: Synthesis, In silico, and In Vitro Analysis

Introduction: The rising prevalence of cancers with chronic inflammation is a leading global health concern. Modern anticancer treatments require dual inhibitors of cyclooxygenase- 2 (COX-2) and Epidermal Growth Factor Receptor (EGFR) with minimal adverse effects. Methods: The emergence of diaryl ether derivatives has encouraged the development of new therapeutic strategies for inflammation-linked conditions. A series of nine diaryl ether derivatives was designed, and in silico studies were performed to predict their interactions with COX- 1, COX-2, and EGFR proteins. Drug likeness and toxicity characteristics were investigated using Swiss ADME, ADMET Lab 2.0, and ProTox-3.0 tools. Furthermore, to observe the selective COX-2 inhibitory nature, a protein (bovine serum albumin (BSA)) denaturation study of the five best compounds with high binding affinities was conducted. Results: Nine diaryl ether derivatives were synthesized and characterized using 1H-NMR, 13C NMR, LC-MS, and FT-IR spectroscopy. Based on the docking score and pharmacokinetics, compound 12a showed a significant IC50 value of 39.24 μg/mL in the BSA denaturation assay. To screen the kinetic behavior of five selected compounds with high binding affinities (11a, 12a, 12b, 12c, and 13a) with COX-2, Molecular Dynamics (MD) simulations were performed for 100 ns. MD simulations and binding free energy calculations were performed to observe the stability of the best-docked EGFR-12a complex with a docking score of -9.5 kcal/mol. Conclusion: This study focused on the synthesis and biological analysis with theoretical explanations. Overall, diaryl ether derivatives are promising precursors for anti-inflammatory and anticancer drugs in the biomedical field.