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Synthesis and Antibacterial Activity of New N ‐Alkylammonium and Carbonate‐Triazole Derivatives within Desosamine of 14‐ and 15‐Membered Lactone Macrolides
Author(s) -
Janas Anna,
Pecyna Paulina,
Gajecka Marzena,
Bartl Franz,
Przybylski Piotr
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000273
Subject(s) - antibacterial activity , chemistry , lipophilicity , stereochemistry , docking (animal) , potency , antibacterial agent , substituent , clarithromycin , alkylation , organic chemistry , antibiotics , biochemistry , bacteria , biology , in vitro , medicine , genetics , nursing , catalysis
Desosamines of azithromycin (AZM) and clarithromycin (CLA) were modified by N ‐alkylation or nucleophilic substitution at the carbonyl/CuAAC sequence. Biological studies revealed a 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 physicochemical parameters, showed the importance of less bulky and unsaturated substituent for an 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 also have an at least threefold lower cytotoxicity than reference antibiotics at comparable antibacterial activity against the S. pneumoniae clinical strain. Differences in antibacterial effects noted for AZM and CLA salts bearing less bulky N ‐substituents can be better understood when their binding modes in the ribosomal tunnel are considered rather than their common low lipophilicity and excellent water solubility.