Design, synthesis, and structure-activity relationship studies of novel thioether pleuromutilin derivatives as potent antibacterial agents

Chenyu Ling; Liqiang Fu; Suo Gao; Wenjing Chu; Hui Wang; Yanqin Huang; Xiaoyan Chen; Yushe Yang

doi:10.1021/jm500312x

Design, synthesis, and structure-activity relationship studies of novel thioether pleuromutilin derivatives as potent antibacterial agents

J Med Chem. 2014 Jun 12;57(11):4772-95. doi: 10.1021/jm500312x. Epub 2014 May 30.

Authors

Chenyu Ling¹, Liqiang Fu, Suo Gao, Wenjing Chu, Hui Wang, Yanqin Huang, Xiaoyan Chen, Yushe Yang

Affiliation

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.

PMID: 24874438
DOI: 10.1021/jm500312x

Abstract

A series of novel thioether pleuromutilin derivatives incorporating various heteroaromatic substituents into the C14 side chain have been reported. Structure-activity relationship (SAR) studies resulted in compounds 52 and 55 with the most potent in vitro antibacterial activity among the series (MIC = 0.031-0.063 μg/mL). Further optimization to overcome the poor water solubility of compound 55 resulted in compounds 87, 91, 109, and 110 possessing good in vitro antibacterial activity with increased hydrophilicity. Compound 114, the water-soluble phosphate prodrug of compound 52, was also prepared and evaluated. Among the derivatives, compound 110 showed moderate pharmacokinetic profiles and good in vivo efficacy in both MSSA and MRSA systemic infection models. Compound 110 was further evaluated in CYP450 inhibition assay and displayed intermediate in vitro inhibition of CYP3A4.

MeSH terms

Aminopyridines / chemical synthesis*
Aminopyridines / pharmacokinetics
Aminopyridines / pharmacology
Animals
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / pharmacokinetics
Anti-Bacterial Agents / pharmacology
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Diterpenes / chemical synthesis*
Diterpenes / pharmacokinetics
Diterpenes / pharmacology
Drug Design
Drug Resistance, Bacterial
Drug Stability
Female
Humans
Hydrophobic and Hydrophilic Interactions
In Vitro Techniques
Male
Methicillin-Resistant Staphylococcus aureus / drug effects
Mice
Microbial Sensitivity Tests
Pleuromutilins
Polycyclic Compounds
Rats
Rats, Sprague-Dawley
Solubility
Staphylococcal Infections / drug therapy
Staphylococcus / drug effects*
Streptococcus / drug effects*
Structure-Activity Relationship
Sulfides / chemical synthesis*
Sulfides / pharmacokinetics
Sulfides / pharmacology

Substances

14-O-(((5-((4-hydroxylpiperidin-1-yl)acetamido)pyridin-3-yl)sulfanyl)acetyl)mutilin
Aminopyridines
Anti-Bacterial Agents
Cytochrome P-450 CYP3A Inhibitors
Diterpenes
Polycyclic Compounds
Sulfides
Cytochrome P-450 CYP3A
CYP3A4 protein, human