Amide prodrugs of NSAIDs: Synthesis and biological evaluation with a hydrolysis study

The aim of the present study was to synthesize prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation and bleeding) associated with their use. A total of six amide-based prodrugs (Ia-f) of aceclofenac, diclofenac, fenbufen, indomethacin, mefenamic acid and 4-biphenyl acetic acid were synthesized through one-pot method (single step synthesis). The structures of the synthesized prodrugs were confirmed by modern analytical techniques. The release pattern of parent drug from prodrug Ia was also studied by reverse phase HPLC method in acidic buffer (pH 1.2), phosphate buffer (pH 7.4), 80% plasma, 10% rat intestinal homogenate and 10% rat liver homogenate (pH 7.4). The prodrugs were also evaluated for their anti-inflammatory and ulcerogenic actions and compared to their corresponding parent drugs.