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

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


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.

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Quinazolines / chemical synthesis
  • Quinazolines / chemistry
  • Quinazolines / pharmacology*
  • Staphylococcus aureus / drug effects*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrahydrofolate Dehydrogenase / metabolism*


  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Quinazolines
  • 2,4-diaminoquinazoline
  • Tetrahydrofolate Dehydrogenase