Tricyclic 1,5-naphthyridinone oxabicyclooctane-linked novel bacterial topoisomerase inhibitors as broad-spectrum antibacterial agents-SAR of left-hand-side moiety (Part-2)
| Autor: | Leo A. Joyce, David E. Kaelin, Peter T. Meinke, Takeshi Shibata, Keith W. Rickert, Masaya Takei, Sangita B. Patel, Changqing Wei, Xiu Wang, Xuanjia Peng, David B. Olsen, Armando Lagrutta, Jun Lu, Masanobu Yajima, Yasumichi Fukuda, Jin Wu, Mitsuhito Shibasaki, Hideyuki Fukuda, Lynn Miesel, Christopher M. Tan, Stephen M. Soisson, Todd A. Black, Ryuta Kishii, Robert F. Smith, Ravi P. Nargund, Edward C. Sherer, Hisashi Takano, Sheo B. Singh, Akinori Nishimura |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular Stereochemistry medicine.drug_class Clinical Biochemistry hERG Pharmaceutical Science Microbial Sensitivity Tests Gram-Positive Bacteria medicine.disease_cause Biochemistry DNA gyrase Cyclooctanes Structure-Activity Relationship Gram-Negative Bacteria Drug Discovery medicine Topoisomerase II Inhibitors Moiety Naphthyridines Molecular Biology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology Chemistry Organic Chemistry Anti-Bacterial Agents DNA Topoisomerases Type II Staphylococcus aureus biology.protein Molecular Medicine Enantiomer Antibacterial activity Topoisomerase inhibitor Tricyclic |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 25:1831-1835 |
| ISSN: | 0960-894X |
| Popis: | Novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of broad-spectrum antibacterial agents targeting bacterial Gyrase A and ParC and have potential utility in combating antibiotic resistance. A series of novel oxabicyclooctane-linked NBTIs with new tricyclic-1,5-naphthyridinone left hand side moieties have been described. Compounds with a ( R )-hydroxy-1,5-naphthyridinone moiety ( 7 ) showed potent antibacterial activity (e.g., Staphylococcus aureus MIC 0.25 μg/mL), acceptable Gram-positive and Gram-negative spectrum with rapidly bactericidal activity. The compound 7 showed intravenous and oral efficacy (ED 50 ) at 3.2 and 27 mg/kg doses, respectively, in a murine model of bacteremia. Most importantly they showed significant attenuation of functional hERG activity (IC 50 >170 μM). In general, lower log D attenuated hERG activity but also reduced Gram-negative activity. The co-crystal structure of a hydroxy-tricyclic NBTI bound to a DNA-gyrase complex exhibited a binding mode that show enantiomeric preference for R isomer and explains the activity and SAR. The discovery, synthesis, SAR and X-ray crystal structure of the left-hand-side tricyclic 1,5-naphthyridinone based oxabicyclooctane linked NBTIs are described. |
| Databáze: | OpenAIRE |
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