Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 10, Pages 4488-4510Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01678
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Funding
- National Natural Science Foundation of China (NSFC) [21172181, 21372186]
- Research Fund for International Young Scientists from International (Regional) Cooperation
- Exchange Program of NSFC [81450110451]
- Chongqing Natural Science Foundation [CSTC2012jjB10026]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [SRFDP 20110182110007]
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A series of novel 3-aminothiazolquinolones as analogues of quinolone antibacterial agents were designed and synthesized in an effort to circumvent quinolone resistance. Among these 3-aminothiazolquinolones, 3-(2-aminothiazol-4yl)-7-chloro-6-(pyrrolidin-1-yl) quinolone 12b exhibited potent antibacterial activity, low cytotoxicity to hepatocyte cells, strong inhibitory potency to DNA gyrase, and a broad antimicrobial spectrum including against multidrug-resistant strains. This active molecule 12b also induced bacterial resistance more slowly than norfloxacin. Analysis of structure activity relationships (SARs) disclosed that the 2-aminothiazole fragment at the 3-position of quinolone plays an important role in exerting antibacterial activity. Molecular modeling and experimental investigation of aminothiazolquinolone 12b with DNA from a sensitive methicillin-resistant Staphylococcus aureus (MRSA) strain revealed that the possible antibacterial mechanism might be related to the formation of a compound 12b-Cu2+-DNA ternary complex in which the Cu2+ ion acts as a bridge between the backbone of 3-aminothiazolquinolone and the phosphate group of the nucleic acid.
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