55686-24-3Relevant articles and documents
A new model of binding of rifampicin and its amino analogues as zwitterions to bacterial RNA polymerase
Pyta, Krystian,Przybylski, Piotr,Klich, Katarzyna,Stefanska, Joanna
, p. 8283 - 8297,15 (2012/12/12)
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. 1H-15N HSQC and 1H-15N HMBC in combination with 1H-1H COSY and 1H-13C 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. 1H-1H 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 1 and comparison of these data with those for 3-13 indicated 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.
