N'-substituted-2'-O,3'-N-carbonimidoyl bridged macrolides: novel anti-inflammatory macrolides without antimicrobial activity.
Macrolide antibiotics, like erythromycin, clarithromycin, and azithromycin, possess anti-inflammatory properties. These properties are considered fundamental to the efficacy of these three macrolides in the treatment of chronic inflammatory diseases like diffuse panbronchiolitis and cystic fibrosis. However, long-term treatment with macrolide antibiotics presents a considerable risk for promotion of bacterial resistance. We have examined antibacterial and anti-inflammatory effects of a novel macrolide class: N'-substituted 2'-O,3'-N-carbonimidoyl bridged erythromycin-derived 14- and 15-membered macrolides. A small focused library was prepared, and compounds without antimicrobial activity, which inhibited IL-6 production, were selected. Data analysis led to a statistical model that could be used for the design of novel anti-inflammatory macrolides. The most promising compound from this library retained the anti-inflammatory activity observed with azithromycin in lipopolysaccharide-induced pulmonary neutrophilia in vivo. Importantly, this study strongly suggests that antimicrobial and anti-inflammatory activities of macrolides are independent and can be separated, which raises development plausibility of novel anti-inflammatory therapeutics.
GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, Zagreb, Croatia. martina.bosnar@glpg.com
Martina
M
Bosnar
Goran
G
Kragol
Sanja
S
Koštrun
Ines
I
Vujasinović
Berislav
B
Bošnjak
Vlatka
V
Bencetić Mihaljević
Zorica
Z
Marušić Ištuk
Samra
S
Kapić
Boška
B
Hrvačić
Karmen
K
Brajša
Branka
B
Tavčar
Dubravko
D
Jelić
Ines
I
Glojnarić
Donatella
D
Verbanac
Ognjen
O
Culić
Jasna
J
Padovan
Sulejman
S
Alihodžić
Vesna
V
Eraković Haber
Radan
R
Spaventi
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology / Q000627:therapeutic use; D001988:Bronchiolitis / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D017291:Clarithromycin / Q000494:pharmacology / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy; D004347:Drug Interactions / Q000276:immunology; D024881:Drug Resistance, Bacterial / Q000276:immunology; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006192:Haemophilus Infections / Q000188:drug therapy; D006193:Haemophilus influenzae / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000009:adverse effects; D008168:Lung / Q000276:immunology; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D001936:Moraxella catarrhalis / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013291:Streptococcus / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D017963:Azithromycin; D017291:Clarithromycin; D004917:Erythromycin; D008070:Lipopolysaccharides; D018942:Macrolides; D000093242:Interleukin-6 Inhibitors