Synthesis and Biological Evaluation of Mutual Prodrugs of Carboxylic Group Containing Some Non-Steroidal Anti-Inflammatory Drugs and Propyphenazone

Background: The use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) is not up to its potential because of their gastrointestinal side effects. Significant attention has been focused on the growth of bio-reversible derivatives, such as mutual prodrugs, to momentarily mask the acidic group of NSAIDs as a promising means of decreasing or eliminating the GI side effects. The aims of this paper are to synthesize the mutual prodrugs of selected NSAIDs (Ketorolac, niflumic acid, tolfenamic acid) with propyphenazone, a study on their several physicochemical characters, hydrolysis kinetics, antiinflammatory, analgesic activity and ulcerogenicity. Methods: Mutual prodrugs were synthesized and their structures were confirmed and characterized using IR, 1H NMR, 13C NMR, mass spectroscopy and their purity was established by elemental analysis. Synthesized prodrugs were subjected for pharmacokinetic studies, analgesic, anti-inflammatory activities and ulcerogenic index. Results: In vitro hydrolysis study of synthesized prodrugs in enzyme-free simulated intestinal fluid (SIF, pH 7.4) and 80% human plasma showed encouraging hydrolysis rate following first order kinetics while found stable in simulated gastric fluid (SGF, pH 1.2). Considerable decrease in ulcerogenic index and better anti-inflammatory activities were found in most of the cases as compared to their parent drugs. Among all prodrugs, viz. KE and NG showed excellent pharmacological response. A very less irritation to gastric mucosal was observed with the synthesized prodrugs than their parent drugs and can be considered for sustained drug release. Conclusion: Encouraging hydrolysis rate in SIF and 80% human plasma, improved analgesic and anti-inflammatory activities and reduced ulcerogenic liabilities of synthesized prodrugs revealed enhancement in the therapeutic index of the parent drugs. On the basis of above observation, it is concluded that mutual prodrugs approach can be applied to obtain synergistic effect for analgesic and anti inflammatory activities as well as to minimize gastrointestinal toxicity of the drug.