title: Synthesis and properties of macrolones characterized by two ether bonds in the linker.
abstract: In this paper synthesis of macrolones 1-18 starting from azithromycin is reported. Two key steps in the construction of the linker between macrolide and quinolone moiety, are formation of central ether bond by alkylation of unactivated OH group, and formation of terminal C-C bond at 6-position of the quinolone unit. Due to the difficulty in formation of these two bonds the study of alternative synthetic methodologies and optimization of the conditions for the selected routes was required. Formation of C-4''-O-ether bond was completed by modified Michael addition, whereas O-alkylation via diazonium cation proved to be the most effective in formation of the central allylic or propargylic ether bond. Comparison of Heck and Sonogashira reaction revealed the former as preferred route to the C-C bond formation at C(6) position of the quinolone unit. Most of the target compounds exhibited highly favorable antibacterial activity against common respiratory pathogens, without significant cytotoxicity profile when tested in vitro on eukaryotic cell lines.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
authors.forename: Ivana Palej
authors.initials: IP
authors.lastname: Jakopović
authors.forename: Goran
authors.initials: G
authors.lastname: Kragol
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Forrest
authors.forename: Catherine S V
authors.initials: CS
authors.lastname: Frydrych
authors.forename: Vlado
authors.initials: V
authors.lastname: Stimac
authors.forename: Samra
authors.initials: S
authors.lastname: Kapić
authors.forename: Maja Matanović
authors.initials: MM
authors.lastname: Skugor
authors.forename: Marina
authors.initials: M
authors.lastname: Ilijas
authors.forename: Hana Cipcić
authors.initials: HC
authors.lastname: Paljetak
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.forename: David J
authors.initials: DJ
authors.lastname: Holmes
authors.forename: Deirdre M B
authors.initials: DM
authors.lastname: Hickey
authors.forename: Donatella
authors.initials: D
authors.lastname: Verbanac
authors.forename: Vesna
authors.initials: V
authors.lastname: Eraković Haber
authors.forename: Sulejman
authors.initials: S
authors.lastname: Alihodzić
mesh_terms: D017963:Azithromycin / Q000031:analogs & derivatives*; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry*; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry*; D008956:Models, Chemical; D015394:Molecular Structure
chemical_list: D003432:Cross-Linking Reagents; D004987:Ethers; D018942:Macrolides; D017963:Azithromycin