title: Structure-activity relationship studies of new rifamycins containing l-amino acid esters as inhibitors of bacterial RNA polymerases.
abstract: 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.
authors.affiliation: Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Czerwonka
authors.affiliation: Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Domagalska
authors.affiliation: Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.
authors.forename: Krystian
authors.initials: K
authors.lastname: Pyta
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4, 60-781 Poznan, Poland.
authors.forename: Marcelina M
authors.initials: MM
authors.lastname: Kubicka
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4, 60-781 Poznan, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Pecyna
authors.affiliation: Department of Genetics and Pharmaceutical Microbiology, University of Medical Sciences, Swiecickiego 4, 60-781 Poznan, Poland; Institute of Human Genetics, Polish Academy of Science, Strzeszynska 32, 60-479 Poznan, Poland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Gajecka
authors.affiliation: Faculty of Chemistry, A. Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland. Electronic address: piotrp@amu.edu.pl.
authors.forename: Piotr
authors.initials: P
authors.lastname: Przybylski
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004952:Esters / Q000737:chemistry*; D006860:Hydrogen Bonding; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D012294:Rifamycins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D004952:Esters; D012294:Rifamycins; D012321:DNA-Directed RNA Polymerases
keywords: Antibacterial activity; Drug-enzyme model; Rifamycin antibiotics; Spectroscopy; l-amino acid esters