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 β-3,4-dihydroxyphenyl-, α-3,4-dihydroxybenzyl-,
and α-3,4-dihydroxybenzylidene-substituted derivatives, exhibited
complex and varying structure-dependent kinetics of inhibition. Among
irreversible binders, methyl β-(3,4-dihydroxyphenyl)-β-(2-carboxyethyl)­phosphorylpropionate
was observed to be a remarkably reactive inhibitor of Sporosarcina pasteurii urease (kinact/KI = 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 β-(3,4-dihydroxyphenyl)-β-phosphonopropionate,
with Ki* = 0.13 μM, and an atypical
low dissociation rate (residence time τ = 205 min).