Design, synthesis and antibacterial activity of novel pleuromutilin derivatives with 4H-pyran-4-one and pyridin-4-one substitution in the C-14 side chain

A series of novel pleuromutilin derivatives with 4H-pyran-4-one and pyridin-4-one substitution in the C-14 side chain have been designed and synthesized. In vitro antibacterial activity evaluation showed that most of the derivatives exhibited potent antibacterial activity against drug resistant Gram-positive strains. Compounds 12a, 12d, and 28 are the most active derivatives in this series, displaying activity comparable to that of retapamulin and BC-3781. As the metabolic stability of this series is not satisfactory, further modifications are going on to improve their pharmacokinetic profile.

Graphical abstractA series of novel pleuromutilin derivatives with 4H-pyran-4-one and pyridin-4-one substitution in the C-14 side chain have been synthesized. Structure–activity relationship study showed that 4H-pyran-4-one moiety is favored over pyridin-4-one. Among the series, compounds 12a, 12d and 28 exhibited excellent antibacterial activity against selected Gram-positive strains including MRSA, MRSE, and PRSP.Figure optionsDownload full-size imageDownload as PowerPoint slide