Synthesis and use of sulfonamide-, sulfoxide-, or sulfone-containing aminoglycoside–CoA bisubstrates as mechanistic probes for aminoglycoside N-6′-acetyltransferase

Aminoglycoside–coenzyme A conjugates are challenging synthetic targets because of the wealth of functional groups and high polarity of the starting materials. We previously reported a one-pot synthesis of amide-linked aminoglycoside–CoA bisubstrates. These molecules are nanomolar inhibitors of aminoglycoside N-6′-acetyltransferase Ii (AAC(6′)-Ii), an important enzyme involved in bacterial resistance to aminoglycoside antibiotics. We report here the synthesis and biological activity of five new aminoglycoside–CoA bisubstrates containing sulfonamide, sulfoxide, or sulfone groups. Interestingly, the sulfonamide-linked bisubstrate, which was expected to best mimic the tetrahedral intermediate, does not show improved inhibition when compared with amide-linked bisubstrates. On the other hand, most of the sulfone- and sulfoxide-containing bisubstrates prepared are nanomolar inhibitors of AAC(6′)-Ii.

Graphical abstractSelective oxidation of water-soluble sulfides to sulfoxides or sulfones in the presence of multiple funtional groups. The aminoglycoside–CoA conjugates, prepared in two steps, are potent inhibitors of aminoglycoside N-6′-acetyltransferase.Figure optionsDownload full-size imageDownload as PowerPoint slide