title: Conformationally restricted analogs of deoxynegamycin.
abstract: 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.
authors.affiliation: Vicuron Pharmaceuticals, Inc, Department of Chemistry, 34790 Ardentech Court, Fremont, CA 94555, USA. braju@vicuron.com
authors.forename: B
authors.initials: B
authors.lastname: Raju
authors.forename: Sampathkumar
authors.initials: S
authors.lastname: Anandan
authors.forename: Shihai
authors.initials: S
authors.lastname: Gu
authors.forename: Prudencio
authors.initials: P
authors.lastname: Herradura
authors.forename: Hardwin
authors.initials: H
authors.lastname: O'Dowd
authors.forename: Bum
authors.initials: B
authors.lastname: Kim
authors.forename: Marcela
authors.initials: M
authors.lastname: Gomez
authors.forename: Corinne
authors.initials: C
authors.lastname: Hackbarth
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wu
authors.forename: Wen
authors.initials: W
authors.lastname: Wang
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Yuan
authors.forename: Richard
authors.initials: R
authors.lastname: White
authors.forename: Joaquim
authors.initials: J
authors.lastname: Trias
authors.forename: Dinesh V
authors.initials: DV
authors.lastname: Patel
mesh_terms: 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
chemical_list: D000599:Amino Acids, Diamino; C100200:negamycin