Abstract
Helicobacter pylori produces ammonia to help counter the acidic environment in the human stomach. The production of ammonia, essential for the microorganism's survival and virulence, is the product of enzymatic conversion of urea by the H. pylori's urease. Inhibition of urease activity by dipeptide hydroxamic acids has previously been demonstrated using a variety of fluorides, thiols and hydroxamic acids. Studies employing computer-aided drug design techniques have been utilized to suggest a novel series of heterocyclic hydroxamic acid derivatives as potential as urease inhibitors. The heterocyclic compounds 7a,b, 10b, 12b, 16b, and 19b have been designed, synthesized, and preliminarily tested as dipeptide mimics which offer a structure that is more biologically stable than that of the reported dipeptide inhibitors.
Acknowledgments
JSW gratefully acknowledges the Chemical Computing Group (Montreal, Quebec) for use of the MOE modeling software, and Dr. Abby L. Parrill (University of Memphis) for help with the computer design methods. Financial support for this project was provided in part by grants from the Centers for Disease Control CDC U50-CCU418839 and CDC UR3-CCU418652.