Synthesis and in vitro kinetic study of novel mutual azo prodrug for inflammatory bowel disease

Background: Inflammatory bowel disease (IBD) refers to idiopathic inflammatory diseases of the intestine, principally ulcerative colitis and Crohn’s disease. IBD is characterized by chronic inflammation in the mucosal membrane of large intestine. 5- ASA is the gold standard for the treatment of IBD and when searched for a better 5- ASA prodrug, a novel mutual azo prodrug was designed and synthesized. Methods: A mutual prodrug was synthesized by coupling p-phenetidine with salicylic acid. The stability of this prodrug in HCl buffer, in phosphate buffer and in rat fecal matter were monitored. Results: The chemical structure of mutual prodrug was characterized by physical and spectroscopic techniques using FTIR, UV/Visible, 1H-NMR and 13C-NMR spectra. In vitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-ASA and p-phenetidine, whereas in phosphate buffer (pH 7.4) only (22.04 %) release was observed over a period of (6 hr.). In rat fecal matter, the hydrolysis of mutual prodrug was almost complete (77.96 %), with a half-life of 182.67 min, following zero order kinetics. Conclusion: The mutual prodrug was split in colon by the action of bacterial azoreductase into 5-ASA and p-phenetidine that constitute two anti-inflammatory compounds with different mechanisms of action. Therefore, this mutual prodrug is a promising colon specific prodrug for IBD and worthy of further study.