Covalent Inhibition Of Bacterial Urease By Bifunctional Catechol-Based Phosphonates And Phosphinates

In this study, a new class of bifunctional inhibitors of bacterial ureases, important molecular targets for antimicrobial therapies, was developed. The structures of the inhibitors consist of a combination of a phosphonate or (2-carboxyethyl)phosphinate functionality with a catechol-based fragment, which are designed for complexation of the catalytic nickel ions and covalent bonding with the thiol group of Cys322, respectively. Compounds with three types of frameworks, including beta-3,4-dihydroxyphenyl-, alpha-3,4-dihydroxybenzyl-, and alpha-3,4-dihydroxybenzylidene-substituted derivatives, exhibited complex and varying structure-dependent kinetics of inhibition. Among irreversible binders, methyl beta-(3,4-dihydroxyphenyl)-beta-(2-carboxyethyl)phosphorylpropionate was observed to be a remarkably reactive inhibitor of Sporosarcina pasteurii urease (k(inact)/K-I = 10 420 s(-1) M-1). The high potential of this group of compounds was also confirmed in Proteus mirabilis whole-cell-based inhibition assays. Some compounds followed slow-binding and reversible kinetics, e.g., methyl beta-(3,4-dihydroxyphenyl)-beta-phosphonopropionate, with K-i* = 0.13 mu M, and an atypical low dissociation rate (residence time tau = 205 min).