Investigating the Bioactivity of Indole-Based Oxadiazole Derivatives: Design, Synthesis, and Anti-Inflammatory Activities.
INTRODUCTION/OBJECTIVE Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) exert their pharmacological effects by inhibiting Cyclooxygenase (COX) enzymes and are widely used in the treatment of inflammation. The new potential anti-inflammatory agents of indolebased oxadiazole derivatives were developed. METHODS A structure-activity relationship study of 62 indomethacin derivatives was designed, synthesized, and tested for COX-2 inhibition and anti-inflammatory activity in vitro. The structures were confirmed by 1H-NMR, 13C-NMR, and ESI-MS. Drug-likeness and pharmacokinetic properties were predicted by PreADME. Molecular docking was conducted to explore the binding interactions of these compounds with COX-2. RESULTS Compounds 4a and 4f exhibited superior COX-2 inhibitory activity compared to indomethacin and celecoxib at a concentration of 500 nM. Compounds 4a and 4f (0.0001-1 μM) showed no cytotoxicity while inhibiting COX-2 in the Raw264.7 cell line. Molecular docking results indicated that compounds 4a and 4f have affinity and interaction with COX-2. CONCLUSION Compounds 4a and 4f show selective COX-2 inhibition as potent antiinflammatory agents for the treatment of inflammatory diseases. Molecular docking studies have shown high affinity for COX-2, and the pharmacokinetic properties suggest that 4f can be categorized as a drug-like compound. Compounds 4a and 4f can be considered for further investigation.