title: A new model of binding of rifampicin and its amino analogues as zwitterions to bacterial RNA polymerase.
abstract: Seven new benzyl (3-9) and four new phenethyl (10-13) amino analogues of ansa-macrolide rifampicin (1) were synthesized using the optimised method of reductive amination. Structures of 3-13 in solution were determined by 1D and 2D NMR and FT-IR methods whereas the energetically most favoured conformation of amino analogues was calculated with the use of the PM5 method. Spectroscopic and semi-empirical studies revealed the presence of zwitterionic forms of all 3-13 analogues in solutions containing water traces. (1)H-(15)N HSQC and (1)H-(15)N HMBC in combination with (1)H-(1)H COSY and (1)H-(13)C HMBC two dimensional spectroscopic methods unambiguously evidenced that the presence of the zwitterionic form of ansa-macrolides was a consequence of proton transfer from the O(8)-H phenolic group to the secondary amine moiety within 3-13 structures. (1)H-(1)H NOESY studies indicated two different orientations of the substituent introduced at the C(3) position for benzyl and phenethyl amino analogues of rifampicin and their similar conformation within the ansa-bridges in solution. FT-IR studies of the deprotonation of molecule and comparison of these data with those for indicated 3-13 C(8)=O double bond character after formation of zwitterions in solution. Results of an antibacterial test against Gram-(-) and Gram-(+) strains were compared with detailed structural information on new analogues of 3-13 to indicate some structure-activity relationships. Molecular recognition studies of 1 and 12 inhibitors at the binding site of bacterial RNA polymerase (RNAP) as zwitterions revealed key intermolecular interactions and led to the proposition of a new model of RNAP inhibition, which explains significant differences in antibacterial properties of rifampicin and its analogues.
authors.affiliation: Faculty of Chemistry, A. Mickiewicz University, Poznan, Poland.
authors.forename: Krystian
authors.initials: K
authors.lastname: Pyta
authors.forename: Piotr
authors.initials: P
authors.lastname: Przybylski
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Klich
authors.forename: Joanna
authors.initials: J
authors.lastname: Stefańska
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D015394:Molecular Structure; D012329:RNA, Bacterial / Q000187:drug effects; D012293:Rifampin / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D017550:Spectroscopy, Fourier Transform Infrared; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D012329:RNA, Bacterial; D012321:DNA-Directed RNA Polymerases; D012293:Rifampin