Isothiazoloquinolones containing functionalized aromatic hydrocarbons at the 7-position: synthesis and in vitro activity of a series of potent antibacterial agents with diminished cytotoxicity in human cells.
This report describes 9H-isothiazolo[5,4-b]quinoline-3,4-diones (ITQs) containing aromatic groups at the 7-position that were prepared using palladium-catalyzed cross-coupling and tested against a panel of susceptible and resistant bacteria. In general, these compounds were more effective against Gram-positive than Gram-negative organisms. Many of the ITQs were more potent than contemporary quinolones and displayed a particularly strong antistaphylococcal activity against a clinically important, multi-drug-resistant strain. In contrast with ITQs reported previously, several of the analogues described in this Letter demonstrated low cytotoxic activity against a human cell line.
Wiles
Jason A
JA
Achillion Pharmaceuticals, Inc., 300 George Street, New Haven, CT 06511-6653, USA. jwiles@achillion.com
Wang
Qiuping
Q
Lucien
Edlaine
E
Hashimoto
Akihiro
A
Song
Yongsheng
Y
Cheng
Jijun
J
Marlor
Christopher W
CW
Ou
Yangsi
Y
Podos
Steven D
SD
Thanassi
Jane A
JA
Thoma
Christy L
CL
Deshpande
Milind
M
Pucci
Michael J
MJ
Bradbury
Barton J
BJ
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D001391:Azo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D002460:Cell Line; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D013438:Sulfhydryl Compounds / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D001391:Azo Compounds; D006841:Hydrocarbons, Aromatic; D011804:Quinolines; D013438:Sulfhydryl Compounds