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

2011; Elsevier BV; Volume: 46; Issue: 8 Linguagem: Inglês

10.1016/j.ejmech.2011.05.002

1768-3254

Andrea Fajdetić, Adrijana Vinter, Hana Čipčić Paljetak, Jasna Padovan, Ivana Palej Jakopović, Samra Kapić, Sulejman Alihodžić, Darko Filić, Marina Modrić, N. Košutić-Hulita, Roberto Antolović, Zrinka Ivezić Schoenfeld, Stjepan Mutak, Vesna Eraković, Radan Spaventi,

Pneumonia and Respiratory Infections

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.