13292-22-3Relevant articles and documents
Intramolecular proton transfer impact on antibacterial properties of ansamycin antibiotic rifampicin and its new amino analogues
Pyta, Krystian,Przybylski, Piotr,Wicher, Barbara,Gdaniec, Maria,Stefanska, Joanna
, p. 2385 - 2388 (2012)
Intramolecular proton transfer in rifampicin (1) and its analogues 2-9 with the formation of zwitterions has been indicated by multinuclear NMR and crystallographic studies. Biological tests of 1-9 in combination with the analysis of ligand-protein intera
The reason for an increase in decomposition of rifampicin in the presence of isoniazid under acid conditions
Singh,Mariappan,Sharda,Kumar,Chakraborti
, p. 405 - 410 (2000)
The poor bioavailability of rifampicin from fixed-dose combinations containing isoniazid has been attributed to isoniazid-catalysed degradation under acid conditions in the stomach. The mechanism by which isoniazid enhances rifampicin degradation is not known. The aim of this study was to determine the role of isoniazid in rifampicin decomposition. Degradation studies were performed in 0.1 M HCl at 37°C, in absence and presence of isoniazid. Both rifampicin and isoniazid were analysed. The degradation of rifampicin was increased approximately threefold in the presence of isoniazid. Isoniazid itself was degraded to a lesser extent amounting to one-fifth of the fall of rifampicin. HPLC studies revealed that decomposition of rifampicin in acidic conditions in the absence of isoniazid stopped at the formation of 3-formylrifamycin, while the reaction in the presence of isoniazid proceeded to form a hydrazone between 3-formylrifamycin and isoniazid. The existence of hydrazone was confirmed by its isolation on a preparative column and comparison with an authentic sample synthesized from reaction of 3-formylrifamycin with isoniazid. We suggest that once 3-formylrifamycin is formed, it interacts with isoniazid to form the hydrazone, through a fast second-order reaction. As hydrazones are unstable in acid conditions, 3-formylrifamycin and isoniazid are regenerated in a reversible manner through a slower first-order reaction. In this complex reaction process, rifampicin is further degraded, while isoniazid is recovered.
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.
