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Synthesis of α-Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases
J. Frydrych, J. Skácel, M. Šmídková, H. Mertlíková-Kaiserová, M. Dračínský, R. Gnanasekaran, M. Lepšík, M. Soto-Velasquez, VJ. Watts, Z. Janeba,
Language English Country Germany
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Persistent link
https://www.medvik.cz/link/bmc19035482
- MeSH
- Adenylate Cyclase Toxin antagonists & inhibitors MeSH
- Antigens, Bacterial MeSH
- Bacterial Proteins antagonists & inhibitors MeSH
- Bacterial Toxins antagonists & inhibitors MeSH
- Cell Line MeSH
- Adenylyl Cyclase Inhibitors chemistry pharmacology MeSH
- Protein Conformation MeSH
- Humans MeSH
- Macrophages cytology drug effects MeSH
- Nucleosides chemistry pharmacology MeSH
- Organophosphonates chemistry pharmacology MeSH
- Molecular Docking Simulation MeSH
- Protein Binding MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel α-branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC50 >10 μm) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5-haloanthraniloyl-substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 362 nm.
References provided by Crossref.org
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