title: Structure-activity relationships of bivalent aminoglycosides and evaluation of their microbiological activities.
abstract: A library of 4,5- and 4,6-linked bivalent aminoglycoside (AMG) antibiotics consisting of neamine and nebramine pharmacophores have been synthesized. We probed the effect of the linker on antibiotic activity with a series of selected synthetic analogues with varied length and substituents. A number of compounds demonstrated in vitro activity against several bacterial strains and showed activity against drug resistant strains of Pseudomonas aeruginosa. Among the compounds prepared, analogues 12a-d were novel 4,6-linked AMGs containing the nebramine pharmacophore. In addition the lead compound OPT-11 possessed an ED(50) of <or=5mg/kg in a Staphylococcus aureus ATCC 29213 mouse protection model.
authors.affiliation: Department of Chemistry, Optimer Pharmaceuticals, Inc., 10110 Sorrento Valley Rd., Suite C, San Diego, CA 92121, USA.
authors.forename: Chang-Hsing
authors.initials: CH
authors.lastname: Liang
authors.forename: Alex
authors.initials: A
authors.lastname: Romero
authors.forename: David
authors.initials: D
authors.lastname: Rabuka
authors.forename: Paulo W M
authors.initials: PW
authors.lastname: Sgarbi
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Marby
authors.forename: Jonathan
authors.initials: J
authors.lastname: Duffield
authors.forename: Sulan
authors.initials: S
authors.lastname: Yao
authors.forename: Mayling L
authors.initials: ML
authors.lastname: Cheng
authors.forename: Yoshi
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Pamela
authors.initials: P
authors.lastname: Sears
authors.forename: Changyong
authors.initials: C
authors.lastname: Hu
authors.forename: San-Bao
authors.initials: SB
authors.lastname: Hwang
authors.forename: Youe-Kong
authors.initials: YK
authors.lastname: Shue
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Sucheck
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000302:isolation & purification; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents