Pyrazolidine-3,5-diones and 5-Hydroxy-1H-pyrazol-3(2H)-ones, Inhibitors of UDP-N-acetylenolpyruvyl Glucosamine Reductase

• Published in: Journal of medicinal chemistry 2006-10, Vol.49 (20), p.6027-6036
• Main Authors: Gilbert, Adam M, Failli, Amedeo, Shumsky, Jay, Yang, Youjun, Severin, Anatoly, Singh, Guy, Hu, William, Keeney, David, Petersen, Peter J, Katz, Alan H
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Candida albicans - drug effects; Carbohydrate Dehydrogenases - antagonists & inhibitors; Enterococcus faecalis - drug effects; Escherichia coli - drug effects; Escherichia coli - enzymology; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Peptidoglycan - biosynthesis; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Staphylococcus aureus - drug effects; Streptococcus - drug effects; Streptococcus - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060499t

A series of pyrazolidine-3,5-dione and 5-hydroxy-1H-pyrazol-3(2H)-one inhibitors of Escherichia coli UDP-N-acetylenolpyruvyl glucosamine reductase (MurB) has been prepared. The 5-hydroxy-1H-pyrazol-3(2H)-ones show low micromolar IC50 values versus E. coli MurB and submicromolar minimal inhibitory concentrations (MIC) against Staphylococcus aureus GC 1131, Enterococcus faecalis GC 2242, Streptococcus pneumoniae GC 1894, and E. coli GC 4560 imp, a strain with increased outer membrane permeability. None of these compounds show antimicrobial activity against Candida albicans, a marker of eukaryotic toxicity. Moreover, these compounds inhibit peptidoglycan biosynthesis, as assessed by measuring the amount of soluble peptidoglycan produced by Streptococcus epidermidis upon incubation with compounds. A partial least squares projection to latent structures analysis shows that improving MurB potency and MIC values correlate with increasing lipophilicity of the C-4 substituent of the 5-hydroxy-1H-pyrazol-3(2H)-one core. Docking studies using FLO and PharmDock produced several binding orientations for these molecules in the MurB active site.