Design, Synthesis, and Anti-Inflammatory Activity of Some Coumarin Schiff Base Derivatives: In silico and in vitro Study

Introduction: Inflammation is a fundamental response of the immune system during tissue damage or pathogen infection to protect and maintain tissue homeostasis. However, inflammation may lead to life-threatening conditions. The most common treatment of inflammation is non-steroidal anti-inflammatory drugs (NSAIDs). Nowadays, the development of safer new NSAIDs is critical as most of the existing NSAIDs have serious adverse effects, such as gastrointestinal (GI) toxicity and cardiotoxicity. In the present study, four compounds as Schiff base derivatives of 7-hydroxy-4-formyl coumarin and 7-methoxy-4-formyl coumarin were designed and synthesized aiming to develop a lead compound that exhibits anti-inflammatory activity and circumvents the side effects of NSAIDs, especially GI toxicity. Materials and Methods: Lipinski's rule of five was applied for each designed molecule to evaluate the drug-likeness properties. Molecular docking studies were performed using the ligands and the cyclooxygenase-2 (COX-2) protein to select the best-scored molecule using AutoDock 4.2.6. The molecules were then synthesized and characterized. An in vitro anti-inflammatory assay of the compounds against the COX-2 receptor was realized through a protein denaturation assay. Results and Discussion: All four synthesized ligands passed Lipinski's rule of five and exhibited higher binding free energy compared to the positive standard control (ibuprofen), and the Ki values of compounds 5, 7, and 8 were in the nanomolar range. However, only compounds 6 and 7 obtained a higher percentage of inhibition of protein denaturation relative to ibuprofen. Conclusion: The present study suggested that compound 7 may be a lead molecule because this ligand not only exhibited the best computational and experimental results but also exhibited the strongest correlation between the concentration and percentage of protein denaturation (R = 0.986 and R-2 = 0.972) with the lowest P-value (0.014).

Automated summary

This study aimed to design and synthesize a compound with anti-inflammatory activity while avoiding the side effects of NSAIDs. Through computational and experimental results, compound 7 was found to be a potential lead molecule with strong anti-inflammatory activity and correlation with protein denaturation.