Novel ureas and thioureas of 15-membered azalides with antibacterial activity against key respiratory pathogens

Abstract The new ureas and thioureas of 15-membered azalides, N ″-substituted 9a-( N ′-carbamoyl-γ-aminopropyl) ( 4 ), 9a-( N ′-thiocarbamoyl-γ-aminopropyl) ( 6 ), 9a-[ N ′-(β-cyanoethyl)- N ′-(carbamoyl-γ-aminopropyl)] ( 8 ) and 9a-[ N ′-(β-cyanoethyl)- N ′-(thiocarbamoyl-γ-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 .