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


Background: Inflammatory bowel disease (IBD) refers to idiopathic inflammatorydiseases of the intestine, principally ulcerative colitis and Crohn’s disease. IBD ischaracterized 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 withsalicylic acid. The stability of this prodrug in HCl buffer, in phosphate buffer and inrat fecal matter were monitored.Results: The chemical structure of mutual prodrug was characterized by physical andspectroscopic techniques using FTIR, UV/Visible, 1H-NMR and 13C-NMR spectra. Invitro kinetic studies in HCl buffer (pH 1.2) showed negligible release of 5-ASA andp-phenetidine, whereas in phosphate buffer (pH 7.4) only (22.04 %) release wasobserved over a period of (6 hr.). In rat fecal matter, the hydrolysis of mutual prodrugwas almost complete (77.96 %), with a half-life of 182.67 min, following zero orderkinetics.Conclusion: The mutual prodrug was split in colon by the action of bacterialazoreductase into 5-ASA and p-phenetidine that constitute two anti-inflammatorycompounds with different mechanisms of action. Therefore, this mutual prodrug is apromising colon specific prodrug for IBD and worthy of further study.