Structure–activity relationship studies of new rifamycins containing l-amino acid esters as inhibitors of bacterial RNA polymerases

• Published in: European journal of medicinal chemistry Vol. 116; pp. 216 - 221
• Main Authors: Czerwonka, Dominika, Domagalska, Joanna, Pyta, Krystian, Kubicka, Marcelina M., Pecyna, Paulina, Gajecka, Marzena, Przybylski, Piotr
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 30.06.2016
• Subjects: Amino Acids - chemistry; Antibacterial activity; DNA-Directed RNA Polymerases - antagonists & inhibitors; DNA-Directed RNA Polymerases - chemistry; DNA-Directed RNA Polymerases - metabolism; Drug-enzyme model; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Esters - chemistry; Hydrogen Bonding; l-amino acid esters; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - enzymology; Microbial Sensitivity Tests; Molecular Conformation; Molecular Docking Simulation; Rifamycin antibiotics; Rifamycins - chemistry; Rifamycins - metabolism; Rifamycins - pharmacology; Spectroscopy; Staphylococcus epidermidis - drug effects; Staphylococcus epidermidis - enzymology; Structure-Activity Relationship; Spectroscopy; Drug-enzyme model; Antibacterial activity; Rifamycin antibiotics; l-amino acid esters
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.03.061

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 μg/mL), comparable to that of rifampicin. SAR for the novel derivatives was discussed in view of the calculated structures of rifamycin-RNAP complexes. [Display omitted] •Syntheses of twelve new rifamycins containing l-amino acid esters have been performed.•NMR and DFT studies revealed two types of new rifamycins' structures in solution.•Low and high potency of basic and aromatic l-amino acid derivatives, respectively.•7 showed favorable lipophilicity and mode of binding to bacterial RNA polymerase.•Potency of the most active 7 is ∼0.02 nmol/mL against Gram-(+) bacteria strains.