Synthesis and structure-activity relationships of truncated bisubstrate inhibitors of aminoglycoside 6'-N-acetyltransferases.

Feng Gao, Xuxu Yan, Tushar Shakya, Oliver M Baettig, Samia Ait-Mohand-Brunet, Albert M Berghuis, Gerard D Wright, Karine Auclair

Index: J. Med. Chem. 49(17) , 5273-81, (2006)

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Abstract

Truncated aminoglycoside-coenzyme A bisubstrate analogues were efficiently prepared using a convergent approach where the amine and the thiol are coupled in one pot with the addition of a linker, without the need for protecting groups. These derivatives were tested for their effect on the activity of the resistance-causing enzyme aminoglycoside 6'-N-acetyltransferase Ii, and key structure-activity relationships are reported. Moreover, one of the inhibitors is able to block aminoglycoside resistance in cells expressing this enzyme.