title: Synthesis of novel 15-membered 8a-azahomoerythromycin A acylides: Consequences of structural modification at the C-3 and C-6 position on antibacterial activity.
abstract: A novel series of 6-O-substituted 8a-aza-8a-homoerythromycin A 3-O-acylides has been discovered with potent activity against key respiratory pathogens, including those inducibly and constitutively resistant to erythromycin. The best compounds in this series 15na and 15nd showed activity comparable to telithromycin, especially against Haemophilus influenzae and constitutively MLSB-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes. Furthermore, 15na exhibited a number of drug-like attributes including favorable pharmacokinetic properties and in vivo efficacy. For instance, 15na exhibited good oral bioavailability (average F = 42%) and demonstrated in vivo efficacy superior to telithromycin (1) against erythromycin-susceptible S. pneumoniae. As such, 15na has a significant potential for further development of this novel macrolide antibiotics class.
authors.affiliation: PLIVA Research Institute, Prilaz Baruna Filipovića 29, 10000 Zagreb, Croatia. Electronic address: drazenpavlovic@rcsi.ie.
authors.forename: Dražen
authors.initials: D
authors.lastname: Pavlović
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland.
authors.forename: Scott
authors.initials: S
authors.lastname: Kimmins
authors.affiliation: PLIVA Research Institute, Prilaz Baruna Filipovića 29, 10000 Zagreb, Croatia.
authors.forename: Stjepan
authors.initials: S
authors.lastname: Mutak
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D024881:Drug Resistance, Bacterial / Q000187:drug effects*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: C544242:8a-aza-8a-homoerythromycin; D000900:Anti-Bacterial Agents; D018942:Macrolides; D004917:Erythromycin
keywords: Acylides; Antibacterial activity; Heck reaction; Macrolide antibiotics; Macrolide resistance; Structure-activity relationships