Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines
| Autor: | Xiaoming Li, Mark Hilgers, Mark Cunningham, Zhiyong Chen, Michael Trzoss, Junhu Zhang, Lucy Kohnen, Thanh Lam, Chris Creighton, Kedar GC, Kirk Nelson, Bryan Kwan, Mark Stidham, Vickie Brown-Driver, Karen J. Shaw, John Finn |
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| Rok vydání: | 2011 |
| Předmět: |
Drug
Models Molecular Staphylococcus aureus media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Microbial Sensitivity Tests medicine.disease_cause Crystallography X-Ray Biochemistry Microbiology chemistry.chemical_compound Structure-Activity Relationship Antibiotic resistance Drug Discovery Dihydrofolate reductase medicine Potency heterocyclic compounds Enzyme Inhibitors Molecular Biology media_common biology Dose-Response Relationship Drug Molecular Structure Chemistry Aryl Organic Chemistry Stereoisomerism Trimethoprim Anti-Bacterial Agents Tetrahydrofolate Dehydrogenase Drug Design biology.protein Quinazolines Molecular Medicine Antibacterial activity medicine.drug |
| Zdroj: | Bioorganicmedicinal chemistry letters. 21(18) |
| ISSN: | 1464-3405 |
| Popis: | Dihydrofolate reductase (DHFR) inhibitors such as trimethoprim (TMP) have long played a significant role in the treatment of bacterial infections. Not surprisingly, after decades of use there is now bacterial resistance to TMP and therefore a need to develop novel antibacterial agents with expanded spectrum including these resistant strains. In this study, we investigated the optimization of 2,4-diamnoquinazolines for antibacterial potency and selectivity. Using structure-based drug design, several 7-aryl-2,4-diaminoquinazolines were discovered that have excellent sub-100 picomolar potency against bacterial DHFR. These compounds have good antibacterial activity especially on gram-positive pathogens including TMP-resistant strains. |
| Databáze: | OpenAIRE |
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