Τίτλος:
Covalent Inhibition of Bacterial Urease by Bifunctional Catechol-Based Phosphonates and Phosphinates
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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). © 2020 American Chemical Society.
Συγγραφείς:
Pagoni, A.
Grabowiecka, A.
Tabor, W.
Mucha, A.
Vassiliou, S.
Berlicki, Ł.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
1 (3,4 dihydroxyphenyl) 2 methoxycarbonylethyl(2 carboxyethyl)phosphinic acid; 1 (3,4 dihydroxyphenyl) 2 methoxycarbonylethylphosphonic acid; 1 (3,4 dihydroxyphenyl)bis(2 carboxyethyl)phosphinic acid; 1 (3,4 dihydroxyphenyl)bis(2 methoxycarbonylethyl)phosphinic acid; 2 carboxy 3 (3,4 dihydroxyphenyl)allyl(2 carboxyethyl)phosphinic acid; 2 carboxy 3 (3,4 dihydroxyphenyl)allylphosphonic acid; 2 carboxy 3 (3,4 dihydroxyphenyl)propyl(2 carboxyethyl)phosphinic acid; 2 carboxy 3 (3,4 dihydroxyphenyl)propylphosphonic acid; 2 ethoxycarbonyl 3 (3,4 dihydroxyphenyl)propyl(2 carboxyethyl)phosphinic acid; 3 (3,4 dihydroxyphenyl) 2 ethoxycarbonylpropylphosphonic acid; 3 (3,4 dihydroxyphenyl) 2 methoxycarbonylallyl(2 carboxyethyl)phosphinic acid; 3 (3,4 dihydroxyphenyl) 2 methoxycarbonylallylphosphonic acid; 3 (3,4 dimethoxyphenyl) 2 methoxycarbonylallylphosphonic acid; bacterial enzyme; catechol; nickel; phosphinic acid derivative; phosphonic acid derivative; thiol group; unclassified drug; urea; urease; urease inhibitor; catechol; catechol derivative; phosphonic acid derivative; urease, antimicrobial therapy; Article; cell suspension; controlled study; covalent bond; crystal structure; decomposition; dissociation rate constant; drug design; drug synthesis; enzyme activity; enzyme inhibition; IC50; inhibition constant; molecular model; nonhuman; Proteus mirabilis; rate constant; Sporosarcina pasteurii; bacterium; enzymology; structure activity relation, Bacteria; Catechols; Organophosphonates; Structure-Activity Relationship; Urease
DOI:
10.1021/acs.jmedchem.0c01143
