Highly Active Oligoethylene\nGlycol Pleuromutilins\nvia Systematic Linker Synthesis/One-Pot Attachment and a Microscale\nSolubility Method

The semisynthetic\nderivatization of natural products is crucial\nfor their continued development as antibiotics. While commercial pleuromutilin\nderivatives depend on amines for solubility, we demonstrate the high\nactivity and solubility of oligoethylene glycol-substituted pleuromutilins\nachieved via a one-pot deprotection/attachment approach using thiolates\nprotected as thioesters. The bifunctional linker synthesis is versatile\nand can be broadly applied to other chemistries. Antibacterial assays\nrevealed this simple glycolate modification enhanced inhibition 4–8-fold\nrelative to that of pleuromutilin. A new microscale solubility method\nis also introduced.