title: Water-soluble phosphate prodrugs of pleuromutilin analogues with potent in vivo antibacterial activity against Gram-positive pathogens.
abstract: 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 (>50mg/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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 20103, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Fu
authors.forename: Zhiteng
authors.initials: Z
authors.lastname: Jiang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Cai
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Huili
authors.initials: H
authors.lastname: He
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004224:Diterpenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D051379:Mice; D008826:Microbial Sensitivity Tests; D010710:Phosphates / Q000737:chemistry*; D011083:Polycyclic Compounds; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013203:Staphylococcal Infections / Q000188:drug therapy; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D010710:Phosphates; D011083:Polycyclic Compounds; D011355:Prodrugs; D014867:Water; D000097567:Pleuromutilins