Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria
| Autor: | Woll Matthew G, Marla Weetall, Jiashi Wang, Sean M. Smith, Arthur Branstrom, Aleksey I. Gerasyuto, Neil Gregory Almstead, Xiaoyan Zhang, Srinivasa Peddi, Guangming Chen, J V N Prasad, Nanjing Zhang, Jana Narasimhan, Josephine Sheedy, Michael Arnold, Melissa Dumble, Gary Mitchell Karp, John D. Baird |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Protein Conformation Pyridines Topoisomerase IV 030106 microbiology Microbial Sensitivity Tests medicine.disease_cause 01 natural sciences DNA gyrase Article Microbiology Mice Structure-Activity Relationship 03 medical and health sciences Drug Resistance Multiple Bacterial Sepsis Gram-Negative Bacteria Drug Discovery medicine Animals Topoisomerase II Inhibitors Structure–activity relationship Escherichia coli Molecular Structure biology 010405 organic chemistry Chemistry Topoisomerase biology.organism_classification Anti-Bacterial Agents Addition/Correction 3. Good health 0104 chemical sciences Acinetobacter baumannii Multiple drug resistance DNA Topoisomerases Type II biology.protein Molecular Medicine Female Bacteria |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure–activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC90 values against Escherichia coli (0.5–1 μg/mL) and Acinetobacter baumannii (8–16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli. |
| Databáze: | OpenAIRE |
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