Download MendeleyStructure-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., G C, K., Nelson, K., Kwan, B., Stidham, M., Brown-Driver, V., Shaw, K.J., Finn, J.(2011) Bioorg Med Chem Lett 21: 5171-5176
- PubMed: 21831637
- DOI: https://doi.org/10.1016/j.bmcl.2011.07.059
- Primary Citation of Related Structures:
3SQY, 3SR5, 3SRQ, 3SRR, 3SRS, 3SRU, 3SRW - PubMed 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.
Organizational Affiliation:
Trius Therapeutics, San Diego, CA 92121, United States.
