Harnessing Hybrid Chemistry: Novel Ethyl Ferulate Ester of Niflumic Acid for Enhanced Therapeutic Benefits

ABSTRACT Niflumic acid is a potent NSAID, while its long‐term therapy can cause gastrointestinal complications. This study explores the prodrug approach of niflumic acid with natural antioxidant ethyl ferulate to improve its pharmacokinetics, thereby reducing gastrointestinal side effects. The primary objective was to develop niflumic acid prodrug with reduced gastric irritation, establish synthetic methods, characterize the prodrug, and evaluate their pharmacological activities. The prodrug was synthesized using the Steglich esterification method and characterized by IR, NMR, mass spectrometry, and elemental analysis. Further, in vitro hydrolysis, partition coefficient determination, protein binding studies, and in silico ADMET prediction were carried out. The pharmacological evaluation encompassed in vitro cytotoxicity assessments, anti‐arthritic investigations, and in vivo studies on anti‐inflammatory and ulcerogenic effects. The hydrolysis of the prodrug resulted in the release of niflumic acid in both simulated gastric fluid and simulated intestinal fluid, adhering to first‐order kinetics, with a half‐life of 230.4 min. Results showed that the prodrug exhibited higher lipophilicity, reduced gastric discomfort, and improved anti‐inflammatory, cytotoxic, and anti‐arthritic activities compared with niflumic acid. The bioconjugation of niflumic acid with ethyl ferulate significantly reduced gastrointestinal side effects while maintaining or enhancing therapeutic efficacy. The findings indicate that the synthesized prodrug represents a promising candidate for the advancement of safer and more effective anti‐inflammatory therapies.