Effects of lawsone and lawsone methyl ether on cyclooxygenase activity, redox balance, and organ-specific toxicity: An integrated computational and experimental study.

Redox imbalance contributes significantly to the initiation and progression of inflammatory responses. Although conventional anti-inflammatory drugs are widely used, their prolonged administration is associated with a number of adverse effects. Lawsone methyl ether (LME) and lawsone are plant-derived, redox-active naphthoquinones, exhibiting diverse pharmacological activities; however, their cyclooxygenase (COX)-inhibitory effects, redox-modulatory properties, and oral toxicity profiles remain insufficiently characterized. Therefore, this study investigated the COX-inhibitory activity, redox-modulatory effects, and oral toxicity profiles of LME and lawsone using integrated computational, enzyme-inhibitory, and in vivo approaches. Molecular docking analysis revealed favorable binding scores/interactions of LME against COX-1 (-5.9 kcal/mol), lipoxygenase (LOX; -6.6 kcal/mol), NAD(P)H oxidase (-5.6 kcal/mol), and myeloperoxidase (MPO; -4.7 kcal/mol), surpassing lawsone and reference inhibitors (aspirin, and zileuton). These results were further validated by molecular dynamics (MD) simulations. Additionally, LME exhibited higher in vitro inhibition of COX-1 (IC50: 8.1 µM) and COX-2 (IC50: 4.2 µM) than lawsone. Furthermore, acute (50/300 mg/kg) and subacute (50 mg/kg) oral administration of LME in Wistar rats significantly ameliorated glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid-reactive substance (TBARS) levels, more effectively than lawsone. Following Karber's method, oral LD50 values calculated for LME and lawsone were 542 and 175 mg/kg, respectively. However, in a 28-day repeated oral toxicity study, a no-observed-adverse-effect level (NOAEL) of at least 50 mg/kg was established for both the compounds, with no toxicity observed across various rat parameters. Overall, LME was better tolerated than lawsone, exhibiting COX inhibitory and redox-modulatory effects, but its therapeutic significance requires further validation.