US EPA

1860121 

Journal Article 

INHIBITION OF HELICOBACTER-PYLORI UREASE BY PHENYL PHOSPHORODIAMIDATES - MECHANISM OF ACTION 

Faraci, WS; Yang, BWV; Orourke, D; Spencer, RW 

1995 

Yes 

Bioorganic & Medicinal Chemistry
ISSN: 0968-0896
EISSN: 1464-3391 

3 

5 

605-610 

7648208 

10.1016/0968-0896(95)00043-G 

WOS:A1995RA97400014 

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(=0)(NH2)(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 pK(a) (e.g. R = NO2, k(1) = 2.5 x 10(5) M(-1)s(-1); R = OMe, k(1) = 1.2 x 10(4) M(-1)s(-1)). The Bronsted beta for inhibition is 0.4, similar to that of model system S(N)2(P) reactions. Based on these observations, we suggest that urease inhibition is covalent but reversible, involving a common phosphoacyl enzyme intermediate.