4LEK: Structure-based Design Of New Dihydrofolate Reductase Antibacterial Agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines

A new series of dihydrofolate reductase (DHFR) inhibitors, the 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines, were designed and optimized for antibacterial potency and enzyme selectivity. The most potent inhibitors in this series contained a five-membered heterocycle at the 2-position of the benzimidazole, leading to highly potent and selective compounds that exploit the differences in the size of a binding pocket adjacent to the NADPH cofactor between the bacterial and human DHFR enzymes. Typical of these compounds is 7-((2-thiazol-2-yl)benzimidazol-1-yl)-2,4 diaminoquinazoline, which is a potent inhibitor of S. aureus DHFR (Ki = 0.002 nM) with 46700-fold selectivity over human DHFR. This compound also has high antibacterial potency on Gram-positive bacteria with an MIC versus wild type S. aureus of 0.0125 mug/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 mug/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series.
PDB ID: 4LEKDownload
MMDB ID: 117664
PDB Deposition Date: 2013/6/25
Updated in MMDB: 2014/03
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4LEK: monomeric; determined by author and by software (PISA)
Molecular Components in 4LEK
Label Count Molecule
Protein (1 molecule)
Dihydrofolate Reductase
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB