Novel 3-Aminothiazolquinolones: Design, Synthesis, Bioactive Evaluation, SARs, and Preliminary Antibacterial Mechanism
† Institute of Bioorganic& Medicinal Chemistry, Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
‡ Department of Public Security Technology, Railway Police College, Zhengzhou 450053, China
J. Med. Chem., 2016, 59 (10), pp 4488–4510
DOI: 10.1021/acs.jmedchem.5b01678
Publication Date (Web): April 26, 2016
Copyright © 2016 American Chemical Society
Abstract
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-4-yl)-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.
Supporting Information
(i) . The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.5b01678.
- Emission spectra of HSA with compound 12b at 303 and 310 K. Isolating genomic DNA from MRSA bacteria. HRMS, 1H NMR, and 13C NMR spectra for some important compounds (PDF)
- Molecular formula strings (CSV)
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