Discovery of a Colon-Targeted Prodrug As an Escherichia coli Biofilm Inhibitor for Treating Inflammatory Bowel Disease.

We hypothesized that the formation of biofilms contributes to the onset of inflammatory bowel disease and, thus, attempted to develop biofilm inhibitors as potential treatment options. We identified a compound (1) with biofilm inhibitory activity in vitro; however, its rate of delivery to the target site, the colon, was low due to its high lipophilicity and low solubility. To improve the colon delivery rate, we considered a prodrug approach through glucuronidation. The glucuronide (3) showed a significant improvement in the in vivo colon delivery rate by avoiding absorption in the small intestine through a reduction in membrane permeability. Furthermore, in a murine disease model featuring dextran sulfate sodium-induced colitis, we confirmed that compound 3 increased the length of the colon approximately three times more than compound 1 did on a dosage basis.