Antibiotics - rifamycins

Primary drug Secondary drug ANTIBIOTICS - RIFAMYCINS analgesics Effect Mechanism Precautions 

RIFAMYCINS ANTACIDS 1 rifamycin levels 1 absorption Separate doses by 2-3 hours 

RIFAMPICIN AMIODARONE L levels of amiodarone Uncertain, but rifampicin is a known enzyme inducer and may therefore t metabolism of amiodarone Watch for a poor response to amiodarone 

RIFAMPICIN DISOPYRAMIDE Disopyramide levels are 1 by rifampicin Rifampicin induces hepatic metabolism of disopyramide Watch for poor response to disopyramide check serum levels if necessary 

RIFAMPICIN mexiletine Rifampicin l mexiletine levels Uncertain postulated that rifampicin may t mexiletine metabolism Watch for poor response to mexiletine 

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The antibiotic rifamycin provides an example of a different and more common situation in which a target structure which has no overall symmetry has imbedded within it a Ci-symmetrical or nearly symmetrical substructure that, in turn, can be converted retrosynthetically to either a C2-symmetrical precursor or a pair of precursors available from a common intermediate. 6... 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

The FhuA receptor of E. coli transports the hydroxamate-type siderophore ferrichrome (see Figure 9), the structural similar antibiotic albomycin and the antibiotic rifamycin CGP 4832. Likewise, FepA is the receptor for the catechol-type siderophore enterobactin. As monomeric proteins, both receptors consist of a hollow, elliptical-shaped, channel-like 22-stranded, antiparallel (3-barrel, which is formed by the large C-terminal domain. A number of strands extend far beyond the lipid bilayer into the extracellular space. The strands are connected sequentially using short turns on the periplasmic side, and long loops on the extracellular side of the barrel. 

Ward, T.J., Dann III, C., and Blaylock, A., Enantiomeric resolution using the macrocyclic antibiotics rifamycin B and rifamycin SV as chiral selectors for capillary electrophoresis, J. Chromatogr. A, 715, 337, 1995. 

The antibiotic rifamycin (Box 28-A) appears to interfere with initiation by competing for the binding of the initial purine nucleoside 5 -triphosphate. The same bacterial RNAP that synthesizes mRNA also transcribes both rRNA and the tRNAs. Thus, the synthesis of all forms of RNA is inhibited by rifamycin. When a population of bacteria is subjected to this antibiotic, a few individuals survive. These rifamycin-resistant mutants are no longer sensitive to the antibiotic. Among them are some mutants that produce an... 

Rifampicin is a synthetic derivative of a naturally occurring antibiotic, rifamycin, that inhibits bacterial DNA-dependent RNA polymerase but not T7 RNA polymerase or eukaryotic RNA polymerases. It binds tightly to the ft subunit. Although it does not prevent promoter binding or formation of the first phosphodiester bond, it effectively prevents synthesis of longer RNA chains. It does not inhibit elongation when added after initiation has occurred. Another antibiotic, streptolydigin, also binds to the ft subunit it inhibits all bond formation. 

The observed complex CD of the antibiotic rifamycin chromophore was simulated (250-190 nm) by means of coupled oscillator theory, from coupling of the long-axis polarized aromatic transition with dienone transition312. 

This reaction played a key role in a highly stereocontrolled synthesis of the aliphatic segment 1 of the antibiotic rifamycin S (2),2 as formulated in equation (III). In each of the two Cr(II) mediated reactions, the desired aldol is essentially the only product isolated. Further studies3 indicate that the 2,3-stereoselectivity is sensitive to the large substituent a to the aldehyde. A cyclic acetal group appears to play a specific role in contrast to an acyclic group, but the factors controlling stereoselectivity are not well understood. 

The antibiotic rifamycin and a semisynthetic derivative, rifampicin, specifically inhibit the initiation of RNA synthesis by interfering with the formation of the first phosphodiester bond of the RNA chain. The elongation of chains already being synthesized is unaffected. 

The antibiotics rifamycin SV and rifampicin reduce Sulfobromophthalein (BSP) elimination in humans. Using injected oocytes, Vavricka et al. (2002) demonstrated that rifampcin is transported by OATP-C and OATP8 and that both rifampicin and rifamycin SV inhibit OATP-C, 8, -B and -A mediated BSP uptake. These results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin S V and rifampicin on hepatic organic anion elimination. 

A,A-Bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride (BOP-Cl, 64) has been found to be an efficient macrolactamization reagent [69]. Tatsuta and coworkers [69c] used it in the synthesis of the ansamycin antibiotic rifamycin W 123). As shown in Scheme 41, amino acid 121 was cyclized to 122 using 4 equiv of BOP-Cl and 10 equiv of diisopropylethylamine in toluene at 85 °C for 3 h. Upon deprotection and oxidation 123 was obtained in 30% yield from 121. 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

In the studies of the synthesis of the ansamycin antibiotic rifamycin S (13S), Corey and Clark [76] found numerous attempts to effect the lactam closure of the linear precursor 132 to 134 uniformly unsuccessful under a variety of experimental conditions, e.g. via activated ester with imidazole and mixed benzoic anhydride. The crux of the problem was associated with the quinone system which so deactivates the amino group to prevent its attachment to mildly activated carboxylic derivatives. Cyclization was achieved after conversion of the quinone system to the hydroquinone system. Thus, as shown in Scheme 45, treatment of 132 with 10 equiv of isobutyl chloroformate and 1 eqtuv of triethylamine at 23 °C produced the corresponding mixed carbonic anhydride in 95% yield. The quinone C=C bond was reduced by hydrogenation with Lindlar catalyst at low temperature. A cold solution of the hydroquinone was added over 2 h to THF at 50 °C and stirred for an additional 12 h at the same temperature. Oxidation with aqueous potassium ferricyanide afforded the cyclic product 134 in 80% yield. Kishi and coworkers [73] gained a similar result by using mixed ethyl carbonic anhydride. 

Category Antibiotic, rifamycin Half-life 45 hours... 

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