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New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Aug 15; Vol. 26 (16), pp. 3988-93. Date of Electronic Publication: 2016 Jun 30. - Publication Year :
- 2016
-
Abstract
- The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36μM, was not cytotoxic when tested on Vero cells (IC50>100μM). To complement the in vitro screening, we also studied the interaction of the test compounds with β-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
Acetyltransferases metabolism
Animals
Anti-Bacterial Agents chemical synthesis
Anti-Bacterial Agents toxicity
Binding Sites
Candida albicans drug effects
Catalytic Domain
Cell Survival drug effects
Chlorocebus aethiops
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors toxicity
Escherichia coli drug effects
Escherichia coli Proteins metabolism
Fatty Acid Synthase, Type II antagonists & inhibitors
Fatty Acid Synthase, Type II metabolism
Hydrogen Bonding
Microbial Sensitivity Tests
Molecular Docking Simulation
Oxadiazoles chemical synthesis
Oxadiazoles chemistry
Oxadiazoles toxicity
Static Electricity
Structure-Activity Relationship
Vero Cells
Acetyltransferases antagonists & inhibitors
Anti-Bacterial Agents chemistry
Enzyme Inhibitors chemistry
Escherichia coli enzymology
Escherichia coli Proteins antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 26
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 27426865
- Full Text :
- https://doi.org/10.1016/j.bmcl.2016.06.089