Identification of (N-aryl-N-arylsulfonyl)aminoacetohydroxamic acids as novel urease inhibitors and the mechanism exploration.

[Display omitted] • (N -Aryl- N -arylsulfonyl)aminoacetohydroxamic acids were identified as novel urease inhibitors. • The novel inhibitors inhibit urease with a mixed mechanism and show no perceptible cytotoxicity. • The most active compound showed over 690-fold higher potency than the clinical used urease inhibitor. • The novel inhibitors bound urease active site with a "Y"-like shape. Thirty-three (N -aryl- N -arylsulfonyl)aminoacetohydroxamic acids were synthesized in an effort to develop novel urease inhibitors. Among these compounds, 2-(N -(3-nitrophenyl)- N -(4- tert -butylphenylsulfonyl))aminoacetohydroxamic acid (e2) exhibited excellent inhibitory activity against Helicobacter pylori urease with no perceptible cytotoxicity to mammalian cells. Compound e2 showed over 690-fold higher potency than the clinical used urease inhibitor acetohydroxamic acid, reversibly inhibiting urease with a mixed mechanism. Molecular modeling revealed that (N -aryl- N -arylsulfonyl)aminoacetohydroxamic acids may possibly bind Ni ions and two hydrophobic regions with a 'Y'-like shape. [ABSTRACT FROM AUTHOR]