Synthesis, Characterization, DFT, and In Silico Investigation of Two Newly Synthesized β-Diketone Derivatives as Potent COX-2 Inhibitors

Despite extensive genetic and biochemical characterization, the molecular genetic basis underlying the biosynthesis of β-diketones remains largely unexplored. β-Diketones and their complexes find broad applications as biologically active compounds. In this study, in silico molecular docking results revealed that two β-diketone derivatives, namely 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione and 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione, exhibit anti-COX-2 activities. However, recent docking results indicated that the relative anti-COX-2 activity of these two studied β-diketones was influenced by the employed docking programs. For improved design of COX-2 inhibitors from β-diketones, we conducted molecular dynamics simulations, density functional theory (DFT) calculations, Hirshfeld surface analysis, energy framework, and ADMET studies. The goal was to understand the interaction mechanisms and evaluate the inhibitory characteristics. The results indicate that 5,5-dimethyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazono)cyclohexane-1,3-dione shows greater anti-COX-2 activity compared to 2-(2-(4-fluorophenyl)hydrazono)-5,5-dimethylcyclohexane-1,3-dione.