Triaminotriazine DNA helicase inhibitors with antibacterial activity.
Screening of a chemical library in a DNA helicase assay involving the Pseudomonas aeruginosa DnaB helicase provided a triaminotriazine inhibitor with good antibacterial activity but associated cytotoxicity toward mammalian cells. Synthesis of analogs provided a few inhibitors that retained antibacterial activity and demonstrated a significant reduction in cytotoxicity. The impact of serum and initial investigations toward a mode of action highlight several features of this class of compounds as antibacterials.
McKay
Geoffrey A
GA
Targanta Therapeutics Inc., 7170 Frederick Banting, 2nd Floor, St. Laurent, Québec, Canada H4S 2A1.
Reddy
Ranga
R
Arhin
Francis
F
Belley
Adam
A
Lehoux
Dario
D
Moeck
Greg
G
Sarmiento
Ingrid
I
Parr
Thomas R
TR
Gros
Philippe
P
Pelletier
Jerry
J
Far
Adel Rafai
AR
D000586:Amination; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D004265:DNA Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D014227:Triazines; D004265:DNA Helicases