Conformationally restricted analogs of deoxynegamycin.
Deoxynegamycin (1b) is a protein synthesis inhibitor with activity against Gram-negative (GN) bacteria. A series of conformationally restricted analogs were synthesized to probe its bioactive conformation. Indeed, some of the constrained analogs were found to be equal or better than deoxynegamycin in protein synthesis assay (1b, IC(50)=8.2 microM; 44, IC(50)=6.6 microM; 35e(2), IC(50)=1 microM). However, deoxynegamycin had the best in vitro whole cell antibacterial activity (Escherichia coli, MIC=4-16 microg/mL; Klebsiella pneumoniae, MIC=8 microg/mL) suggesting that other factors such as permeation may also be contributing to the overall whole cell activity. A new finding is that deoxynegamycin is efficacious in an E. coli murine septicemia model (ED(50)=4.8 mg/kg), providing further evidence of the favorable in vivo properties of this class of molecules.
Raju
B
B
Vicuron Pharmaceuticals, Inc, Department of Chemistry, 34790 Ardentech Court, Fremont, CA 94555, USA. braju@vicuron.com
Anandan
Sampathkumar
S
Gu
Shihai
S
Herradura
Prudencio
P
O'Dowd
Hardwin
H
Kim
Bum
B
Gomez
Marcela
M
Hackbarth
Corinne
C
Wu
Charlotte
C
Wang
Wen
W
Yuan
Zhengyu
Z
White
Richard
R
Trias
Joaquim
J
Patel
Dinesh V
DV
D000599:Amino Acids, Diamino / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D007711:Klebsiella pneumoniae / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D008968:Molecular Conformation
D000599:Amino Acids, Diamino; C100200:negamycin