Water-soluble phosphate prodrugs of pleuromutilin analogues with potent in vivo antibacterial activity against Gram-positive pathogens

A phosphate prodrug strategy was investigated to address the problem of poor aqueous solubility of pleuromutilin analogues. Water-soluble phosphate prodrugs 6a, 6b and 6c of pleuromutilin analogues were designed and synthesized. Three compounds all exhibited excellent aqueous solubility (>50 mg/mL) at near-neutral pH and sufficient stability in buffer solution. In particular, the phenol pleuromutilin prodrug 6c displayed favourable pharmacokinetic profiles and comparable potency with vancomycin against MSSA and MRSA strains in vivo.

Synthesis and biological properties of phosphate prodrugs of pleuromutilin analogues are disclosed. Compound 6c was metabolized efficiently to the biologically active parent 5d in vivo, it also showed excellent antibacterial activity against MSSA and MRSA with comparable ED50 as vancomycin by iv administration in mice.Figure optionsDownload as PowerPoint slide