title: Design, synthesis, and structure-activity relationship studies of novel thioether pleuromutilin derivatives as potent antibacterial agents.
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.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Chenyu
authors.initials: C
authors.lastname: Ling
authors.forename: Liqiang
authors.initials: L
authors.lastname: Fu
authors.forename: Suo
authors.initials: S
authors.lastname: Gao
authors.forename: Wenjing
authors.initials: W
authors.lastname: Chu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Yushe
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004224:Diterpenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004355:Drug Stability; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008826:Microbial Sensitivity Tests; D011083:Polycyclic Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013203:Staphylococcal Infections / Q000188:drug therapy; D013210:Staphylococcus / Q000187:drug effects*; D013291:Streptococcus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000097567:Pleuromutilins
chemical_list: D000631:Aminopyridines; D000900:Anti-Bacterial Agents; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004224:Diterpenes; D011083:Polycyclic Compounds; D013440:Sulfides; D000097567:Pleuromutilins; C000590787:14-O-(((5-((4-hydroxylpiperidin-1-yl)acetamido)pyridin-3-yl)sulfanyl)acetyl)mutilin; C510163:CYP3A4 protein, human