Inhibition of Helicobacter pylori Urease by Phenyl Phosphorodiamidates: Mechanism of Action Original Research Article

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)(NH2)2) are slow-binding inhibitors of H. pylori urease with no evidence of kinetic saturation. Their second-order rates of inhibition k1 are strongly correlated with phenol pKa (e.g. R = NO2, k1 = 2.5 × 105 M−1s−1; R = OMe, k1 = 1.2 × 104 M−1s−1). The Bronsted β for inhibition is 0.4, similar to that of model system SN2(P) reactions. Based on these observations, we suggest that urease inhibition is covalent but reversible, involving a common phosphoacyl enzyme intermediate.