Synthesis and Comparative Analgesic and Anti-Inflammatory Activity of Indolizinyl Derivatives of Some NSAIDs

Indolizine, structurally similar to indoles, is known for various biological activities, including analgesic, anti-inflammatory, hypoglycemic, CNS depressant, antimicrobial, and antioxidant effects. The study aimed to synthesize, indolizine derivatives of NSAIDs such as sodium salicylate, aspirin, mefenamic acid, and flufenamic acid to evaluate their comparative analgesic and anti-inflammatory activities. Pyridine was heated with chloroacetic acid and ethyl acetate at 90°C to form pyridinium halide, which was then refluxed with methyl acrylate, manganese dioxide, triethylamine, and toluene at 90°C to yield indolizine-1-carboxylate. This intermediate was esterified with sodium salicylate, aspirin, mefenamic acid, or flufenamic acid to produce the corresponding indolizine derivatives (INS, INA, INM, INF). These derivatives were characterized by melting point, TLC, IR, NMR, and hydrolysis kinetics, and were screened for analgesic and anti-inflammatory activities. The synthesized indolizinyl derivatives (INS, INA, INM, INF) were evaluated for hydrolysis kinetics at different pH levels, with SS showing the highest cumulative drug release and INF the lowest across pH 1.2, 4.5, 6.8, and 7.4. The derivatives exhibited superior analgesic and anti-inflammatory activities compared to their respective pure drugs, with INM demonstrating the most significant effects among all the derivatives. The novel NSAID derivatives, particularly INM, exhibited significantly enhanced analgesic and anti-inflammatory activities compared to their parent compounds (SS, ASP, MA, FA) showing potential new therapeutic agents for pain and inflammation management.