Negishi cross-coupling enabled synthesis of novel NAD(+)-dependent DNA ligase inhibitors and SAR development
| Autor: | P. Ann Boriack-Sjodin, Lakshmaiah Gingipalli, Madhu Gowravaram, Amy Kutschke, Herbert Oguto, Kerry E. Murphy-Benenato, Sahil Patel, James T. Loch, Michele Johnstone, Dan Carcanague, Charles J. Eyermann, Matthew D. Miller, Harris Jahic, Gabriel Martínez-Botella, Georgine Ioannidis, Valerie A. Laganas, Jenna Harang, Michael R. Hale |
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| Rok vydání: | 2015 |
| Předmět: |
Staphylococcus aureus
Molecular model DNA Ligases Stereochemistry Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests Biochemistry Structure-Activity Relationship Bacterial Proteins Drug Discovery Structure–activity relationship Naphthyridines Molecular Biology chemistry.chemical_classification DNA ligase Negishi coupling Organic Chemistry NAD Haemophilus influenzae Anti-Bacterial Agents Enzyme Pyrimidines Streptococcus pneumoniae chemistry Molecular Medicine NAD+ kinase Pharmacophore |
| Zdroj: | Bioorganicmedicinal chemistry letters. 25(22) |
| ISSN: | 1464-3405 |
| Popis: | Two novel compounds, pyridopyrimidines (1) and naphthyridines (2) were identified as potent inhibitors of bacterial NAD(+)-dependent DNA ligase (Lig) A in a fragment screening. SAR was guided by molecular modeling and X-ray crystallography. It was observed that the diaminonitrile pharmacophore made a key interaction with the ligase enzyme, specifically residues Glu114, Lys291, and Leu117. Synthetic challenges limited opportunities for diversification of the naphthyridine core, therefore most of the SAR was focused on a pyridopyrimidine scaffold. The initial diversification at R(1) improved both enzyme and cell potency. Further SAR developed at the R(2) position using the Negishi cross-coupling reaction provided several compounds, among these compounds 22g showed good enzyme potency and cellular potency. |
| Databáze: | OpenAIRE |
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