Structure-activity relationships of novel 2-substituted quinazoline antibacterial agents.
High-throughput screening of in-house compound libraries led to the discovery of a novel antibacterial agent, compound 1 (MIC: 12-25 microM against S. pyogenes). In an effort to improve the activity of this active compound, a series of 2-substituted quinazolines was synthesized and evaluated in several antibacterial assays. One such compound (22) displayed improved broad-spectrum antibacterial activity against a variety of bacterial strains. This molecule also inhibited transcription/translation of bacterial RNA, suggesting a mechanism for its antibiotic effects. Structure-activity relationship studies of 22 led to the synthesis of another 24 compounds. Although some of these molecules were found to be active in bacterial growth assays, none were as potent as 22. Compound 22 was tested for its ability to cure a systemic K. pneumonia infection in the mouse and displayed moderate effects compared with a control antibiotic, gentamycin.
Kung
P P
PP
Ibis Therapeutics, a Division of Isis Pharmaceuticals, Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, California 92008, USA.
Casper
M D
MD
Cook
K L
KL
Wilson-Lingardo
L
L
Risen
L M
LM
Vickers
T A
TA
Ranken
R
R
Blyn
L B
LB
Wyatt
J R
JR
Cook
P D
PD
Ecker
D J
DJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D007710:Klebsiella Infections / Q000188:drug therapy; D007711:Klebsiella pneumoniae / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D014176:Protein Biosynthesis / Q000187:drug effects; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012329:RNA, Bacterial / Q000235:genetics; D013211:Staphylococcus aureus / Q000187:drug effects; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
C401390:4-(1-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperidin-4-ylamino)benzoic acid; D000900:Anti-Bacterial Agents; D001565:Benzoates; D011799:Quinazolines; D012329:RNA, Bacterial