title: Synthesis of macrolones with central piperazine ring in the linker and its influence on antibacterial activity.
abstract: Three macrolides, clarithromycin, azithromycin and 11-O-Me-azithromycin have been selected for the construction of a series of new macrolone derivatives. Quinolone-linker intermediates are prepared by Sonogashira-type C(6)-alkynylation of 6-iodoquinolone precursors. The final macrolones, differing by macrolide moiety and substituents at the position N-1 of the quinolone or by the presence of an ethyl ester or free acid on the quinolone unit attached via a linker. The linker comprises of a central piperazine ring bonded to the 4″-O position of cladinose by 3-carbon ester or ether functionality. Modifications of the linker did not improve antibacterial properties compared to the previously reported macrolone compounds. Linker flexibility seems to play an important role for potency against macrolide resistant respiratory pathogens.
authors: GlaxoSmithKline Research Centre Zagreb, Croatia. samra.kapic@glpg.com
authors: Samra
authors: S
authors: Kapić
authors: Hana
authors: H
authors: Cipčić Paljetak
authors: Ivana
authors: I
authors: Palej Jakopović
authors: Andrea
authors: A
authors: Fajdetić
authors: Marina
authors: M
authors: Ilijaš
authors: Vlado
authors: V
authors: Stimac
authors: Karmen
authors: K
authors: Brajša
authors: David J
authors: DJ
authors: Holmes
authors: John
authors: J
authors: Berge
authors: Sulejman
authors: S
authors: Alihodžić
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D010879:Piperazines; D015363:Quinolones; D000077489:Piperazine