Novel cyclohexyl-amides as potent antibacterials targeting bacterial type IIA topoisomerases.
As part of our wider efforts to exploit novel mode of action antibacterials, we have discovered a series of cyclohexyl-amide compounds that has good Gram positive and Gram negative potency. The mechanism of action is via inhibition of bacterial topoisomerases II and IV. We have investigated various subunits in this series and report advanced studies on compound 7 which demonstrates good PK and in vivo efficacy properties.
Diseases of the Developing World CEDD, GlaxoSmithKline, Calle Severo Ochoa, 2, 28760, Tres Cantos, Madrid, Spain. tim.j.miles@gsk.com
Timothy J
TJ
Miles
Christopher
C
Barfoot
Gerald
G
Brooks
Pamela
P
Brown
Dongzhao
D
Chen
Steven
S
Dabbs
David T
DT
Davies
David L
DL
Downie
Susanne
S
Eyrisch
Ilaria
I
Giordano
Michael N
MN
Gwynn
Alan
A
Hennessy
Jennifer
J
Hoover
Jianzhong
J
Huang
Graham
G
Jones
Roger
R
Markwell
Stephen
S
Rittenhouse
Hong
H
Xiang
Neil
N
Pearson
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D004285:Dogs; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D000882:Haplorhini; D006801:Humans; D008826:Microbial Sensitivity Tests; D017434:Protein Structure, Tertiary; D051381:Rats; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D000577:Amides; D000900:Anti-Bacterial Agents; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II