Development of Substituted 2‐(2‐(Phenyl)hydrazono)‐5,5‐Dimethylcyclohexane‐1,3‐diones as Possible COX‐2 Inhibitors

Cyclooxygenase‐2 (COX‐2) plays a pivotal role in inflammation and cancer progression, making it a critical therapeutic target for anti‐inflammatory drug development. This study designed and evaluated (computationally) a series of 2‐(2‐(phenyl)hydrazono)‐5,5‐dimethylcyclohexane‐1,3‐dione derivatives (3–6) as possible COX‐2 inhibitors. Molecular docking simulations revealed that compound 5 exhibited the highest binding affinity (−8.9 kcal/mol) compared to ibuprofen (−6.8 kcal/mol). Density functional theory (DFT) calculations and molecular dynamics simulations further confirmed the stability and electronic properties of the COX‐2‐5 complex. ADMET analysis highlighted compound 5 as a promising lead compound, despite some challenges with aqueous solubility and potential CYP enzyme inhibition. These findings may provide a foundation for the development of novel COX‐2 inhibitors with enhanced pharmacological profiles.