title: 6-Alkylquinolone-3-carboxylic acid tethered to macrolides synthesis and antimicrobial profile.
abstract: Two series of clarithromycin and azithromycin derivatives with terminal 6-alkylquinolone-3-carboxylic unit with central ether bond in the linker were prepared and tested for antimicrobial activity. Quinolone-linker intermediates were prepared by Sonogashira-type C(6)-alkynylation of 6-iodo-quinolone precursors. In the last step, 4'' site-selective acylation of 2'-protected macrolides was completed with the EDC reagent, which selectively activated a terminal, aliphatic carboxylic group in dicarboxylic intermediates. Antimicrobial activity of the new series of macrolones is discussed. The most potent compound, 4''-O-{6-[3-(3-carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-propoxy]-hexanoyl}-azithromycin (10), is highly active against bacterial respiratory pathogens resistant to macrolide antibiotics and represents a promising lead for further investigation.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. samra.y.kapic@gsk.com
authors.forename: Samra
authors.initials: S
authors.lastname: Kapić
authors.forename: Hana
authors.initials: H
authors.lastname: Cipcić Paljetak
authors.forename: Sulejman
authors.initials: S
authors.lastname: Alihodzić
authors.forename: Roberto
authors.initials: R
authors.lastname: Antolović
authors.forename: Vesna
authors.initials: V
authors.lastname: Eraković Haber
authors.forename: Richard L
authors.initials: RL
authors.lastname: Jarvest
authors.forename: David J
authors.initials: DJ
authors.lastname: Holmes
authors.forename: John P
authors.initials: JP
authors.lastname: Broskey
authors.forename: Eric
authors.initials: E
authors.lastname: Hunt
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017963:Azithromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D017291:Clarithromycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D018942:Macrolides; D015363:Quinolones; D017963:Azithromycin; D017291:Clarithromycin