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

• Published in: Journal of medicinal chemistry Vol. 57; no. 3; pp. 651 - 668
• Main Authors: Lam, Thanh, Hilgers, Mark T, Cunningham, Mark L, Kwan, Bryan P, Nelson, Kirk J, Brown-Driver, Vickie, Ong, Voon, Trzoss, Michael, Hough, Grayson, Shaw, Karen Joy, Finn, John
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.02.2014; Amer Chemical Soc
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Benzimidazoles - chemical synthesis; Benzimidazoles - pharmacokinetics; Benzimidazoles - pharmacology; Chemistry, Medicinal; Drug Resistance, Bacterial; Folic Acid Antagonists - chemical synthesis; Folic Acid Antagonists - pharmacokinetics; Folic Acid Antagonists - pharmacology; Humans; Life Sciences & Biomedicine; Mice; Microbial Sensitivity Tests; Models, Molecular; Pharmacology & Pharmacy; Quinazolines - chemical synthesis; Quinazolines - pharmacokinetics; Quinazolines - pharmacology; Science & Technology; Sepsis - drug therapy; Staphylococcal Infections - drug therapy; Staphylococcus aureus - drug effects; Staphylococcus aureus - enzymology; Streptococcus pneumoniae - drug effects; Structure-Activity Relationship; Tetrahydrofolate Dehydrogenase - metabolism; BUGS; ANTIFOLATE; RESISTANT STAPHYLOCOCCUS-AUREUS; EFFICIENT; 2,4-DIAMINOQUINAZOLINES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401204g

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 (K i = 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.