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Azithromycin–sulfonamide conjugates as inhibitors of resistantStreptococcus pyogenesstrains

Authors
Journal
European Journal of Medicinal Chemistry
0223-5234
Publisher
Elsevier
Publication Date
Volume
42
Issue
2
Identifiers
DOI: 10.1016/j.ejmech.2006.08.008
Keywords
  • 15-Membered Azalides
  • Azithromycin–Sulfonamide Conjugates
  • Antimicrobial Activity
  • Structural Elucidation
  • Acid Stability

Abstract

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.

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