Synthesis, Biological Evaluation, Molecular Docking and In‐silico ADMET Studies of Mutual Prodrugs of Some Nonsteroidal Anti‐inflammatory Drugs

Abstract The use of NSAIDs is limited due to their gastrointestinal (GI) side‐effects. To mitigate this, substantial research has focused on developing bio‐reversible derivatives like mutual prodrugs to temporarily mask the acidic group of NSAIDs, thereby reducing or eliminating GI toxicity. This study aims to synthesize mutual prodrugs by conjugating propyphenazone with selected NSAIDs (flurbiprofen, mefenamic acid, aspirin, salicylic acid, and aceclofenac), to enhance therapeutic efficacy while minimizing GI side‐effects. Prodrugs were evaluated for in‐vitro COX‐1/COX‐2 inhibitory activities, key players in inflammation. Molecular docking studies were performed to examine binding free energies (ΔG), binding poses, and interactions within COX enzymes’ active sites. Besides, prodrugs were tested for in‐vitro antioxidant activity and in‐vivo anti‐inflammatory, analgesic, and ulcerogenic potential including in‐silico pharmacokinetic properties. Flurbiprofen‐propyphenazone prodrug (compound 4 ) exhibited most potent activity among others, inhibiting COX‐1 (IC 50 = 6.16 ± 0.02 µM) and COX‐2 (IC 50 = 1.19 ± 0.02 µM). Molecular docking revealed key interactions crucial for ligand‐protein stabilization. Compound 4 depicted better anti‐inflammatory and analgesic activities and showed decrease in ulcerogenic index. Antioxidant assay confirmed good radical‐scavenging capabilities. Computational ADMET studies predicted favorable drug‐like properties, making compound 4 a lead candidate for further optimization. These findings underscore the potential of this approach in developing safer NSAIDs for inflammatory disorders.