Article ; Online: New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors.
Bioorganic & medicinal chemistry letters
2016 Volume 26, Issue 16, Page(s) 3988–3993
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 ... ...
| 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. |
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| MeSH term(s) | Acetyltransferases/antagonists & inhibitors ; Acetyltransferases/metabolism ; Animals ; Anti-Bacterial Agents/chemical synthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/toxicity ; Binding Sites ; Candida albicans/drug effects ; Catalytic Domain ; Cell Survival/drug effects ; Cercopithecus aethiops ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/toxicity ; Escherichia coli/drug effects ; Escherichia coli/enzymology ; Escherichia coli Proteins/antagonists & inhibitors ; 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 |
| Chemical Substances | 1,2,5-oxadiazole 2-oxide ; Anti-Bacterial Agents ; Enzyme Inhibitors ; Escherichia coli Proteins ; Oxadiazoles ; Acetyltransferases (EC 2.3.1.-) ; fabH protein, E coli (EC 2.3.1.180) ; Fatty Acid Synthase, Type II (EC 6.-) |
| Language | English |
| Publishing date | 2016--15 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 1063195-1 |
| ISSN | 1464-3405 ; 0960-894X |
| ISSN (online) | 1464-3405 |
| ISSN | 0960-894X |
| DOI | 10.1016/j.bmcl.2016.06.089 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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