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

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 18; pp. 5407 - 5410
• Main Authors: Fu, Liqiang, Jiang, Zhiteng, cai, Zhan, Liu, Xin, He, Huili, Yang, Yushe
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.09.2009; Elsevier
• Subjects: Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Diterpenes - chemistry; Diterpenes - pharmacokinetics; Diterpenes - pharmacology; Gram-positive bacteria; Gram-Positive Bacteria - drug effects; Medical sciences; Mice; Microbial Sensitivity Tests; Pharmacology. Drug treatments; Phosphates - chemistry; Pleuromutilin; Pleuromutilins; Polycyclic Compounds; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Rats; Rats, Sprague-Dawley; Solubility; Staphylococcal Infections - drug therapy; Structure-Activity Relationship; Water - chemistry; Water-soluble phosphate prodrugs; Gram-positive bacteria; Water-soluble phosphate prodrugs; Pleuromutilin; Intravenous administration; Rat; Vancomycin; Organic carbamate; Imide; Bacteria; Micrococcales; Micrococcaceae; Chemical synthesis; Staphylococcus aureus; Terpenoid; Rodentia; Oral administration; Prodrug; Biological activity; Resistance; Water soluble compound; In vivo; Vertebrata; Mammalia; Mouse; Animal; Diterpene; Organic phosphate; Antibacterial agent; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.07.115

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 ED 50 as vancomycin by iv administration in mice. 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.