title: Structure-based design of new DHFR-based antibacterial agents: 7-aryl-2,4-diaminoquinazolines.
abstract: 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.
authors.affiliation: Trius Therapeutics, San Diego, CA 92121, United States.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Hilgers
authors.forename: Mark
authors.initials: M
authors.lastname: Cunningham
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Trzoss
authors.forename: Junhu
authors.initials: J
authors.lastname: Zhang
authors.forename: Lucy
authors.initials: L
authors.lastname: Kohnen
authors.forename: Thanh
authors.initials: T
authors.lastname: Lam
authors.forename: Chris
authors.initials: C
authors.lastname: Creighton
authors.forename: Kedar
authors.initials: K
authors.lastname: G C
authors.forename: Kirk
authors.initials: K
authors.lastname: Nelson
authors.forename: Bryan
authors.initials: B
authors.lastname: Kwan
authors.forename: Mark
authors.initials: M
authors.lastname: Stidham
authors.forename: Vickie
authors.initials: V
authors.lastname: Brown-Driver
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Shaw
authors.forename: John
authors.initials: J
authors.lastname: Finn
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; C013474:2,4-diaminoquinazoline; D013762:Tetrahydrofolate Dehydrogenase