title: Structure-based design of new dihydrofolate reductase antibacterial agents: 7-(benzimidazol-1-yl)-2,4-diaminoquinazolines.
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.
authors.affiliation: Trius Therapeutics Inc. , 6310 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Thanh
authors.initials: T
authors.lastname: Lam
authors.forename: Mark T
authors.initials: MT
authors.lastname: Hilgers
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cunningham
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Kwan
authors.forename: Kirk J
authors.initials: KJ
authors.lastname: Nelson
authors.forename: Vickie
authors.initials: V
authors.lastname: Brown-Driver
authors.forename: Voon
authors.initials: V
authors.lastname: Ong
authors.forename: Michael
authors.initials: M
authors.lastname: Trzoss
authors.forename: Grayson
authors.initials: G
authors.lastname: Hough
authors.forename: Karen Joy
authors.initials: KJ
authors.lastname: Shaw
authors.forename: John
authors.initials: J
authors.lastname: Finn
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018805:Sepsis / Q000188:drug therapy; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013762:Tetrahydrofolate Dehydrogenase