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 ED50 of 5 mg/kg in a Staphylococcus aureus ATCC 29213 mouse protection model.