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Bioorg Med Chem Lett. 2011 Sep 15;21(18):5171-6. doi: 10.1016/j.bmcl.2011.07.059. Epub 2011 Jul 23.

Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.

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Trius Therapeutics, San Diego, CA 92121, United States.


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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