期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 116, 期 -, 页码 216-221出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2016.03.061
关键词
Rifamycin antibiotics; (L)-amino acid esters; Antibacterial activity; Spectroscopy; Drug-enzyme model
资金
- National Science Centre (Poland) [UMO-2011/03/B/ST5/01014]
New rifamycins (1-12) combined with different L-amino acids, containing methyl, ethyl, tert-butyl and benzyl groups at the ester part, via amine linkage, were synthesized and their structures in solution were determined by spectroscopic FT-IR and 1D and 2D NMR methods as well as visualized by DFT calculations. Two types of rifamycin structures were detected in solution: a zwitterionic one with the transferred proton from O(8)H phenol to secondary N(38) atom and a pseudocyclic structure stabilized via formation of intramolecular H-bond within the protonated basic C(3)-substituent. The presence of these rifamycins' structures influenced physico-chemical (logP, solubility) parameters and antibacterial properties. The bulkiness at the ester substituent of new rifamycins containing aromatic (L)-amino acids was found to be an important factor, besides the solubility, to achieve relatively high antibacterial activity against reference S. epidermidis and reference S. aureus and MRSA strains (MICs 0.016-0.063 mu g/mL), comparable to that of rifampicin. SAR for the novel derivatives was discussed in view of the calculated structures of rifamycin-RNAP complexes. (C) 2016 Elsevier Masson SAS. All rights reserved.
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