3srs
S. aureus Dihydrofolate Reductase complexed with novel 7-aryl-2,4-diaminoquinazolinesS. aureus Dihydrofolate Reductase complexed with novel 7-aryl-2,4-diaminoquinazolines
Structural highlights
Function[DYR_STAAU] Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Publication Abstract from PubMedDihydrofolate 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. Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.,Li X, Hilgers M, Cunningham M, Chen Z, Trzoss M, Zhang J, Kohnen L, Lam T, Creighton C, Gc K, Nelson K, Kwan B, Stidham M, Brown-Driver V, Shaw KJ, Finn J Bioorg Med Chem Lett. 2011 Sep 15;21(18):5171-6. Epub 2011 Jul 23. PMID:21831637[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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