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Eur J Med Chem. 2015 Aug 28;101:419-30. doi: 10.1016/j.ejmech.2015.06.047. Epub 2015 Jul 2.

Synthesis and evaluation of isatin-β-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species.

Author information

1
State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
2
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
3
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: daihq@im.ac.cn.
4
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China. Electronic address: zhanglixin@im.ac.cn.
5
State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. Electronic address: nkwjg@nankai.edu.cn.

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) have caused an increasing mortality rate, which means that antibiotic resistance is becoming an important health issue. In the course to screen new agents for resistant bacteria, we identified that a series of isatin-β-thiosemicarbazones (IBTs) could inhibit the growth of MRSA and VRE. This was the first time that the "familiar" IBT compounds exhibited significant anti Gram-positive pathogen activity. Against a clinical isolated MRSA strain, 20 of the 51 synthesized compounds showed minimum inhibitory concentration (MIC) data of 0.78 mg/L and another 12 novel compounds had MICs of 0.39 mg/L. Moreover, these compounds also inhibited Enterococcus faecalis and VRE at similar levels, indicating that IBTs might have different mode of action compared with vancomycin. For these IBTs, comparative field analysis (CoMFA) models were further established to understand the structure-activity relationships in order to design new compounds from steric and electrostatic contributions. This work has suggested that IBTs can be considered as potential lead compounds to discover antibacterial inhibitors to combat drug resistance.

KEYWORDS:

In vitro activity; Isatin-β-thiosemicarbazone; Methicillin-resistant Staphylococcus aureus; Structure–activity relationships; Vancomycin-resistant Enterococcus

PMID:
26185006
DOI:
10.1016/j.ejmech.2015.06.047
[Indexed for MEDLINE]

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