Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: Pharmacophore identification based on the screening hit closantel

This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic require...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1998-07, Vol.8 (14), p.1923-1928
Main Authors: Hlasta, Dennis J., Demers, James P., Foleno, Barbara D., Fraga-Spano, Stephanie A., Guan, Jihua, Hilliard, Jamese J., Macielag, Mark J., Ohemeng, Kwasi A., Sheppard, Cheryl M., Sui, Zhihua, Webb, Glenda C., Weidner-Wells, Michele A., Werblood, Harvey, Barrett, John F.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Biological and medical sciences
Drug Resistance, Microbial
Enterococcus faecium - drug effects
Gram-Positive Bacteria - drug effects
Medical sciences
Microbial Sensitivity Tests
Pharmacology. Drug treatments
Phosphorylation
Salicylanilides - chemistry
Salicylanilides - pharmacology
Staphylococcus aureus - drug effects
Structure-Activity Relationship
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Summary:This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, hydrophobicity is not the sole determinant for inhibition; structural and electronic requirements also exist. Closantel ( 1) was found to inhibit a two-component system and to have antibacterial activity against drug resistant S. aureus and E. faecium. This SAR study has shown that the salicylanilide is the pharmacophore for inhibition of the bacterial two-component system. Hydrophobic substituents improve the potency of inhibitors in this series; however, structural and electronic requirements also exist. Closantel ( 1) is a two-component system inhibitor (IC 50 = 3.8 μM) and has antibacterial activity against drug resistant S. aureus and E. faecium (MICs of 1–2 μg/mL).
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(98)00326-6