Structure−Activity Relationships of Phenyl-Furanyl-Rhodanines as Inhibitors of RNA Polymerase with Antibacterial Activity on Biofilms

• Published in: Journal of medicinal chemistry 2007-08, Vol.50 (17), p.4195-4204
• Main Authors: Villain-Guillot, Philippe, Gualtieri, Maxime, Bastide, Lionel, Roquet, Françoise, Martinez, Jean, Amblard, Muriel, Pugniere, Martine, Leonetti, Jean-Paul
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biofilms; Biological and medical sciences; Cellular Biology; CHO Cells; Cricetinae; Cricetulus; DNA-Directed RNA Polymerases; DNA-Directed RNA Polymerases - antagonists & inhibitors; Escherichia coli; Furans; Furans - chemical synthesis; Furans - pharmacology; Gram-Positive Bacteria; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - isolation & purification; Gram-Positive Bacteria - physiology; Life Sciences; Medical sciences; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Rhodanine; Rhodanine - analogs & derivatives; Rhodanine - chemical synthesis; Rhodanine - pharmacology; Staphylococcus epidermidis; Staphylococcus epidermidis - drug effects; Staphylococcus epidermidis - isolation & purification; Staphylococcus epidermidis - physiology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0703183

The dramatic rise of antibiotic-resistant bacteria over the past two decades has stressed the need for completely novel classes of antibacterial agents. Accordingly, recent advances in the study of prokaryotic transcription open new opportunities for such molecules. This paper reports the structure−activity relationships of a series of phenyl-furanyl-rhodanines (PFRs) as antibacterial inhibitors of RNA polymerase (RNAP). The molecules have been evaluated for their ability to inhibit transcription and affect growth of bacteria living in suspension or in a biofilm and for their propensity to interact with serum albumin, a critical parameter for antibacterial drug discovery. The most active of these molecules inhibit Escherichia coli RNAP transcription at concentrations of ≤10 μM and have promising activities against various Gram-positive pathogens including Staphylococcus epidermidis biofilms, a major cause of nosocomial infection.