Novel ureas and thioureas of 15-membered azalides with antibacterial activity against key respiratory pathogens.
The new ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-gamma-aminopropyl) (4), 9a-(N'-thiocarbamoyl-gamma-aminopropyl) (6), 9a-[N'-(beta-cyanoethyl)-N'-(carbamoyl-gamma-aminopropyl)] (8) and 9a-[N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-gamma-aminopropyl)] (10) of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A (2), were synthesized and structurally characterized by NMR and IR spectroscopic methods and mass spectrometry. The new compounds were evaluated in vitro against a panel of erythromycin susceptible and erythromycin-resistant gram-positive and gram-negative bacterial strains. These compounds displayed an excellent overall antibacterial in vitro activity against erythromycin sensitive gram-positive strains, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and good against negative strains, Moraxella catarrhalis and Haemophilus influenzae. In addition, several ureas with naphthyl substituents (4f, 4g, 4h) showed better activity in comparison to azithromycin against inducible resistant S. pyogenes. Ureas with naphthyl substituents 4g, 4h and thiourea 8h displayed moderate activity against constitutively resistant S. pneumoniae.
Bukvić Krajacić
Mirjana
M
GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia. mirjana.2.bukvic-krajacic@gsk.com
Novak
Predrag
P
Dumić
Miljenko
M
Cindrić
Mario
M
Paljetak
Hana Cipcić
HC
Kujundzić
Nedjeljko
N
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D004355:Drug Stability; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D004917:Erythromycin; D014508:Urea; D013890:Thiourea