Inhibition of Helicobacter pylori Urease by Phenyl Phosphorodiamidates: Mechanism of Action

Abstract

Helicobacter pylori urease is a nickel-containing enzyme that hydrolyzes urea to bicarbonate and ammonia. Andrews et al. ( J. Am. Chem. Soc. 1986, 108, 7124) 1 have shown that amides and esters of phosphoric acid are slow, tight-binding inhibitors of urease isolated from jack bean. We show that 4-substituted phenyl phosphorodiamidates (4-R-PhOP(=O)(NH 2) 2) are slow-binding inhibitors of H. pylori urease with no evidence of kinetic saturation. Their second-order rates of inhibition k 1 are strongly correlated with phenol p K a (e.g. R = NO 2, k 1 = 2.5 × 10 5 M −1s −1; R = OMe, k 1 = 1.2 × 10 4 M −1s −1). The Bronsted β for inhibition is 0.4, similar to that of model system S N2(P) reactions. Based on these observations, we suggest that urease inhibition is covalent but reversible, involving a common phosphoacyl enzyme intermediate.