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  • Title: Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.
    Author: Li X, Hilgers M, Cunningham M, Chen Z, Trzoss M, Zhang J, Kohnen L, Lam T, Creighton C, G C K, Nelson K, Kwan B, Stidham M, Brown-Driver V, Shaw KJ, Finn J.
    Journal: Bioorg Med Chem Lett; 2011 Sep 15; 21(18):5171-6. PubMed ID: 21831637.
    Abstract:
    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.
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