Urease (E.C. 3.5.1.5) is an enzyme, which catalyses the hydrolysis of urea into ammonia and carbamate. Enhanced activity of urease is claimed to be a pathogenic marker in case of many infections of urinal and digestion tracts. This hydrolase is also crucial for the bacterium Helicobacter pylori existence, a pathogen causing stomach ulcers and finally tumors. This fact originates from local increase of pH caused by the catalyzed reaction, forming this way microenvironment suitable for bacterium survival and proliferation. Thus, the development of potent and selective inhibitors of urease provides perspective biomedical applications.

Several classes of compounds are known to show considerable inhibitory activity against urease. Hydroxamic acids have been the most extensively studied, whereas phosphordiamidate and thiophosphordiamidate transition state analogues of the enzymatic reaction are those of the highest activity. However, the main disadvantage of phosphorus acid diamide derivatives is their low stability in water solutions caused by rapid hydrolysis.

Here, we present the rational design, synthesis and enzymatic activity of novel organophosphorus inhibitors of urease. They represent P-methylphosphinate and phosphonamidate analogues of phosphordiamidate phenyl esters. These transition state analogues of improved hydrolytic resistance will serve as new lead compounds for the development of more extended urease inactivators.

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