Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones

被引：27

作者：

Fajdetic, Andrea ^{[1
]}

Vinter, Adrijana ^{[1
]}

Paljetak, Hana Cipcic ^{[1
]}

Padovan, Jasna ^{[1
]}

Jakopovic, Ivana Palej ^{[1
]}

Kapic, Samra ^{[1
]}

Alihodzic, Sulejman ^{[1
]}

Filic, Darko ^{[1
]}

Modric, Marina ^{[1
]}

Kosutic-Hulita, Nada ^{[1
]}

Antolovic, Roberto ^{[1
]}

Schoenfeld, Zrinka Ivezic ^{[1
]}

Mutak, Stjepan ^{[1
]}

Haber, Vesna Erakovic ^{[1
]}

Spaventi, Radan ^{[1
]}

机构：

[1] GlaxoSmithKline Res Ctr Zagreb Ltd, HR-10000 Zagreb, Croatia

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 46卷 / 08期

关键词：

Macrolide; Resistance; Antibacterial activity; Pharmacokinetics; Oral bioavailability; RESISTANT RESPIRATORY PATHOGENS; STREPTOCOCCUS-PNEUMONIAE; ANTIMICROBIAL RESISTANCE; 4''-O-ACYL DERIVATIVES; MACROLIDES; AZALIDES; DESIGN; INHIBITORS; DISCOVERY; KETOLIDES;

D O I：

10.1016/j.ejmech.2011.05.002

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci. (C) 2011 Elsevier Masson SAS. All rights reserved.

引用

页码：3388 / 3397

页数：10

共 33 条

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