1. J Med Chem. 2013 Oct 10;56(19):7691-7705. Epub 2013 Oct 1.

Tuning the Antibacterial Activity of Amphiphilic Neamine Derivatives and
Comparison to Paromamine Homologues.

Zimmermann L, Bussière A, Ouberai M, Baussanne I, Jolivalt C, Mingeot-Leclercq
MP, Décout JL.

Département de Pharmacochimie Moléculaire, Université de Grenoble I/CNRS , UMR
5063, ICMG FR 2607, 470 rue de la Chimie, BP 53, F-38041 Grenoble, France.

Aminoglycosides are antibiotic drugs that act through binding to rRNA. In the
search for antimicrobial amphiphilic aminoglycosides targeting bacterial
membranes, we report here on the discovery of three dialkyl derivatives of the
small aminoglycoside neamine active against susceptible and resistant
Gram-positive and Gram-negative bacteria. One of these derivatives (R =
2-naphthylpropyl), which has good activity against MRSA and VRSA, showed a low
toxicity in eukaryotic cells at 10 μM. The synthesis of amphiphilic paromamine
and neamine homologous derivatives pointed out the role of the 6'-amine function 
of the neamine core in the antibacterial effects. The optimal number of
lipophilic substituents to be attached to the neamine core and the corresponding 
required lipophilicity determined here should permit a more selective targeting
of bacterial membranes relative to eukaryotic membranes. This work revealed the
existence of windows of lipophilicity necessary for obtaining strong
antibacterial effects that should be of interest in the field of antibacterial
amphiphilic aminoglycosides.

PMID: 24083676  [PubMed - as supplied by publisher]