title: Water-soluble pleuromutilin derivative with excellent in vitro and in vivo antibacterial activity against gram-positive pathogens.
abstract: Although earlier pleuromutilin analogues showed potent in vitro antibacterial activity against some Gram-positive pathogens, their in vivo efficacy was low because of insufficient pharmacokinetic properties. We designed novel thioether pleuromutilin derivatives having a purine ring as a polar and water solubilizing group and identified a promising pleuromutilin analogue 6 with good solubility in water ( approximately 50 mg/mL). Compound 6 exhibited excellent in vitro and in vivo antibacterial activity against some Gram-positive strains, including drug-resistant pathogens.
authors.affiliation: Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Enoki 33-94, Suita, Osaka, 564-0053, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Hirokawa
authors.forename: Hironori
authors.initials: H
authors.lastname: Kinoshita
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Nakata
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kitadai
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kashimoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kojima
authors.forename: Shiro
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D016908:Gram-Positive Bacterial Infections / Q000188:drug therapy; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011083:Polycyclic Compounds; D012995:Solubility; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry; D000097567:Pleuromutilins
chemical_list: D000900:Anti-Bacterial Agents; D004224:Diterpenes; D011083:Polycyclic Compounds; D014867:Water; D000097567:Pleuromutilins