A click chemistry approach to pleuromutilin derivatives, part 2: conjugates with acyclic nucleosides and their ribosomal binding and antibacterial activity.

Ida Dreier, Surender Kumar, Helle Søndergaard, Maria Louise Rasmussen, Lykke Haastrup Hansen, Nanna Holmgaard List, Jacob Kongsted, Birte Vester, Poul Nielsen

Index: J. Med. Chem. 5th ed., 55 , 2067-2077, (2012)

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Abstract

Pleuromutilin is an antibiotic that binds to bacterial ribosomes and thereby inhibit protein synthesis. A new series of semisynthetic pleuromutilin derivatives were synthesized by a click chemistry strategy. Pleuromutilin was conjugated by different linkers to a nucleobase, nucleoside, or phenyl group, as a side-chain extension at the C22 position of pleuromutilin. The linkers were designed on the basis of the best linker from our first series of pleuromutilin derivatives following either conformational restriction or an isosteric methylene to oxygen exchange. The binding of the new compounds to the Escherichia coli ribosome was investigated by molecular modeling and chemical footprinting of nucleotide U2506, and it was found that all the derivatives bind to the specific site and most of them better than pleuromutilin itself. The effect of the side-chain extension was also explored by chemical footprinting of nucleotide U2585, and the results showed that all the compounds interact with this position to varying degrees. Derivatives with a conformational restriction of the linker generally had a higher affinity than derivatives with an isosteric exchange of one of the carbons in the linker with a hydrophilic oxygen. A growth inhibition assay with three different bacterial strains showed significant activity of several of the new compounds.