Synthesis and properties of macrolones characterized by two ether bonds in the linker.
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.
Jakopović
Ivana Palej
IP
GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia.
Kragol
Goran
G
Forrest
Andrew K
AK
Frydrych
Catherine S V
CS
Stimac
Vlado
V
Kapić
Samra
S
Skugor
Maja Matanović
MM
Ilijas
Marina
M
Paljetak
Hana Cipcić
HC
Jelić
Dubravko
D
Holmes
David J
DJ
Hickey
Deirdre M B
DM
Verbanac
Donatella
D
Eraković Haber
Vesna
V
Alihodzić
Sulejman
S
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
D003432:Cross-Linking Reagents; D004987:Ethers; D018942:Macrolides; D017963:Azithromycin