Citation: Song Guo-Qing, Wang Wei-Min, Li Zai-Shun, Wang Ying, Wang Jian-Guo. First identification of isatin-β-thiosemicarbazones as novel inhibitors of New Delhi metallo-β-lactamase-1: Chemical synthesis, biological evaluation and molecular simulation[J]. Chinese Chemical Letters, ;2018, 29(6): 899-902. doi: 10.1016/j.cclet.2017.09.035 shu

First identification of isatin-β-thiosemicarbazones as novel inhibitors of New Delhi metallo-β-lactamase-1: Chemical synthesis, biological evaluation and molecular simulation

Song Guo-Qing ^a,1 ,
Wang Wei-Min ^a,c,1 ,
Li Zai-Shun ^a ,
Wang Ying ^b,, ,
Wang Jian-Guo ^a,,

a.
State-Key Laboratory and Research Institute of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, College of Chemistry, Nankai University, Tianjin 300071, China
b.
Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China
c.
Patent Examination Cooperation Jiangsu Center of the Patent Office, SIPO, Suzhou 215163, China

Corresponding author: Wang Ying, ying.wang@htmdc.org Wang Jian-Guo, nkwjg@nankai.edu.cn

Received Date: 30 June 2017
Revised Date: 14 August 2017
Accepted Date: 13 September 2017
Available Online: 15 June 2017

Figures(4)

New Delhi metallo-β-lactmase-1 (NDM-1) catalyzes the hydrolysis of β-lactam antibiotics and cleaves the β-lactam ring of the molecule, conferring bacterial resistance against these medicines. In an effort to discover novel agents to treat this superbug, an old drug methisazone was found to be a weak NDM-1 inhibitor, with an IC₅₀ of 297.6 μmol/L. Based on this result, a series of isatin-β-thiosemicarbazones (IBTs) were synthesized and biologically evaluated as novel NDM-1 inhibitors. Nine of the IBT compounds showed IC₅₀ values of < 10 μmol/L, the best of which was 2.72 μmol/L. Comparative field analysis (CoMFA) contour maps were generated to depict the structural features and molecular docking was performed to understand the possible binding mode of these inhibitors. The present research hereby has provided valuable information for further discovery of NDM-1 inhibitors.
- New Delhi metallo-β-lactmase-1,
- Isatin-β-thiosemicarbazones,
- In vitro enzyme inhibition,
- Molecular docking
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沈阳化工大学材料科学与工程学院沈阳 110142