Structure-activity relationships of bivalent aminoglycosides and evaluation of their microbiological activities.
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.
Liang
Chang-Hsing
CH
Department of Chemistry, Optimer Pharmaceuticals, Inc., 10110 Sorrento Valley Rd., Suite C, San Diego, CA 92121, USA.
Romero
Alex
A
Rabuka
David
D
Sgarbi
Paulo W M
PW
Marby
Kenneth A
KA
Duffield
Jonathan
J
Yao
Sulan
S
Cheng
Mayling L
ML
Ichikawa
Yoshi
Y
Sears
Pamela
P
Hu
Changyong
C
Hwang
San-Bao
SB
Shue
Youe-Kong
YK
Sucheck
Steven J
SJ
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
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents