May 29, 2020

Synthesis and antibacterial activity of new N-alkylammonium and carbonate-triazole derivatives within desosamine of 14- and 15-membered lactone macrolides

ChemMedChem
Anna JanasPiotr Przybylski

Abstract

Desosamine of azithromycin ( AZM ) and clarithromycin ( CLA ) was modified via S N 2 and CuAAC dipolar cycloaddition. The biological studies revealed higher antibacterial potency of quaternary N -alkylammonium bromides of CLA as compared to AZM . SAR studies of CLA salts, including biological, conformation and molecular docking analysis, enriched by physico-chemical parameters, showed the importance of less bulky and unsaturated substituent for efficient docking mode at the ribosomal tunnel and good antibacterial potency against clinical and standard Streptococcus pneumoniae and Streptococcus pyogenes strains (MICs 0.25 or 0.5 µg/mL). These CLA salts have also at least a 3-fold lower cytotoxicity than the reference antibiotics at comparable antibacterial activity against S. pneumoniae clinical strain. Differences in antibacterial effects noted for AZM and CLA salts bearing less bulky N -substituents are better understandable when considering their binding modes in the ribosomal tunnel rather than their common low lipophilicity and excellent water solubility.

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Mentioned in this Paper

Protein Conformation
Azithromycin
Antibiotics
Anti-Bacterial Agents
Nucleocapsid Proteins
Macrolides
Minimum Inhibitory Concentration Result
Docking -molecular Interaction
Clarithromycin
Finding

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