title: Design, synthesis, and in vitro activity of novel 2'-O-substituted 15-membered azalides.
abstract: Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2'-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2'. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia.
authors.forename: Dijana
authors.initials: D
authors.lastname: Pešić
authors.forename: Kristina
authors.initials: K
authors.lastname: Starčević
authors.forename: Ana
authors.initials: A
authors.lastname: Toplak
authors.forename: Esperanza
authors.initials: E
authors.lastname: Herreros
authors.forename: Jaume
authors.initials: J
authors.lastname: Vidal
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Almela
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.forename: Sulejman
authors.initials: S
authors.lastname: Alihodžić
authors.forename: Radan
authors.initials: R
authors.lastname: Spaventi
authors.forename: Mihaela
authors.initials: M
authors.lastname: Perić
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D004351:Drug Resistance; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000962:Antimalarials; D001372:Aza Compounds; D011804:Quinolines; D004917:Erythromycin; D002738:Chloroquine