Substituted Salicylanilides as Inhibitors of Two-Component Regulatory Systems in Bacteria

• Published in: Journal of medicinal chemistry 1998-07, Vol.41 (16), p.2939-2945
• Main Authors: Macielag, Mark J, Demers, James P, Fraga-Spano, Stephanie A, Hlasta, Dennis J, Johnson, Sigmond G, Kanojia, Ramesh M, Russell, Ronald K, Sui, Zhihua, Weidner-Wells, Michele A, Werblood, Harvey, Foleno, Barbara D, Goldschmidt, Raul M, Loeloff, Michael J, Webb, Glenda C, Barrett, John F
• 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; Bacillus subtilis - enzymology; Bacillus subtilis - metabolism; Bacillus subtilis - physiology; Bacterial Proteins - antagonists & inhibitors; Biological and medical sciences; Drug Evaluation, Preclinical; Drug Resistance, Microbial; Enterococcus faecium - drug effects; Enterococcus faecium - enzymology; Enterococcus faecium - genetics; Enterococcus faecium - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Gram-Positive Bacteria - drug effects; Gram-Positive Bacteria - enzymology; Gram-Positive Bacteria - physiology; Luciferases - genetics; Luciferases - metabolism; Medical sciences; Methicillin Resistance; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases - genetics; salicylanilides; Salicylanilides - chemical synthesis; Salicylanilides - chemistry; Salicylanilides - pharmacology; Spores, Bacterial - drug effects; Staphylococcus aureus - drug effects; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Vancomycin - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9803572

A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2,3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6.3 μM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).