4LAG

Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines

Summary for 4LAG

• Entry DOI: 10.2210/pdb4lag/pdb
• Related: 4LAE 4LAH 4LEK
• Descriptor: Dihydrofolate reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-chloro-7-[5,6-dimethyl-2-(1,3-thiazol-2-yl)-1H-benzimidazol-1-yl]quinazoline-2,4-diamine, ... (4 entities in total)
• Functional Keywords: protein-inhibitor complex, folate, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 20512.40

Authors

Hilgers, M.T. (deposition date: 2013-06-19, release date: 2014-02-19, Last modification date: 2024-02-28)

Primary citation

Lam, T.,Hilgers, M.T.,Cunningham, M.L.,Kwan, B.P.,Nelson, K.J.,Brown-Driver, V.,Ong, V.,Trzoss, M.,Hough, G.,Shaw, K.J.,Finn, J.
Structure-Based Design of New Dihydrofolate Reductase Antibacterial Agents: 7-(Benzimidazol-1-yl)-2,4-diaminoquinazolines.
J.Med.Chem., 57:651-668, 2014

PubMed Abstract: 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 μg/mL and a MIC versus trimethoprim-resistant S. aureus of 0.25 μg/mL. In vivo efficacy versus a S. aureus septicemia was demonstrated, highlighting the potential of this new series.

PubMed: 24428639
DOI: 10.1021/jm401204g

Experimental method

X-RAY DIFFRACTION (1.7 Å)