Azithromycin-sulfonamide conjugates as inhibitors of resistant Streptococcus pyogenes strains.

Abstract Novel hybrid compounds 6a – 6d , conjugates of 15-membered azalides and sulfonamides, i.e. unsubstituted, 4-aryl- and 4-heteroaryl-aminosulfonyl derivatives of 9a-[ N ′-(phenylcarbamoyl)]-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A were synthesized and characterized by IR, one- and two-dimensional NMR spectroscopies and MALDI-TOF and MS/MS mass spectrometry. The new compounds were evaluated in vitro against a panel of sensitive and resistant Gram-positive and Gram-negative bacterial strains. 9a-{ N ′-[4-(Aminosulfonyl)phenyl]carbamoyl} – ( 6a ) and 9a-{ N ′-[4-(phenylaminosulfonyl)phenyl]carbamoyl} – ( 6b ) derivatives showed improvements in activity against inducible resistant Streptococcus pyogenes in comparison with macrolide antibiotic azithromycin and starting material 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A ( 2 ). In addition, the synthesized azithromycin–sulfonamide conjugates 6a – 6d showed good antibacterial activity against sensitive S. pyogenes and Streptococcus pneumoniae strains. The kinetics of degradation in the artificial gastric juice showed that the most active compounds, 6a and 6b , exhibited azithromycin like stability. The cleavage of the cladinose sugar was found to be the main decomposition pathway leading to inactive 7a and 7b , prepared also as analytical standards by the alternative synthetic route together with 7c and 7d .