Inhibition of Urease by Cyclic b-Triketones and Fluoride Ions

Competitive inhibition of soybean urease by 11 cyclic b-triketones was studied in aqueous solutions at pH 7.4 and 36C. This process was characterized quantitatively by the inhibition constant (K sub(i)), which showed a strong dependence on the structure of the organic chelating agents (nickel atoms in urease) and varied from 58.4 to 847 kM. Under similar conditions, the substrate analogue (hydroxyurea) acted as a weak urease inhibitor (K sub(i) = 6.47 mM). At 20C, competitive inhibition of urease with the ligand of nickel atoms (fluoride anion) was pH-dependent. At pH 3.85-6.45, the value of K sub(i) for the process ranged from 36.5 to 4060 kM. Three nontoxic cyclic b-triketones with K sub(i) values of 58.4, 71.4, and 88.0 kM (36C) were the most potent inhibitors of urease. Their efficacy was determined by the presence of three >C=O- groups in the molecule and minimum steric hindrances to binding with metal sites in soybean urease.