Rifamycin B derivatives

Brand Name(s) Rifadin, Rifadin IV, Rimactane Chemical Class Rifamycin B derivative... 

Target Molecule 6-Deoxyerythronolide B Erythronolide A Derivative Ansa Chain of Rifamycin B 66 66... 

Scheme 2.1 General synthetic schemes for the immobilization of macrocyclic antibiotics. (a) (i) 1,6-Diisocyanatohexane (ii) glycopeptide (TE, TAG, and A-40,926). (b) (i) Glycopeptide (eremomycin, ristocetin A, vancomycin), (c) (i) NaI04 (ii) glycopeptide (vancomycin, ristocetin A, MDL 63,246). (d) (i) 3-Isocyanatopropyl-silyl derivative of macrocyclic antibiotic (TE, rifamycin B, vancomycin, DMP-vancomycin, NVC).

Rifampin (Fig. 8) is semisynthetic derivative of Rifamycin B that was isolated from Sterptomyces mediterranei. 5 F 52 niode of action was confirmed... 

Rifampicin, a semisynthetic derivative of the antimicrobial agent rifamycin B obtained from Strep-tomyces mediterranei, is bactericidal for intra- and extracellular bacteria. Bacterial RNA synthesis is inhibited by binding to the beta-subunit of DNA-dependent RNA polymerase. Human polymerases are not affected. It has activity against gram-positive and gram-negative cocci, chlamydia as well as mycobacteria. It is used in combination with dapsone for leprosy. 

Chemical Properties and Derivatives. There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader-spectrum antibiotic having good oral absorption. Rifamycins B, O, and S have served as starting materials tor the preparation of numerous classes of derivatives. Several of the semisyntheUc derivatives are more active, have a broader spectrum of biological activity, and are therapeutically more effective than the parent antibiotics. 

The rifamycins were first isolated by Sensi et al.3) from Nocardia mediterranei as a complex mixture (Rifamycins A—E). Addition of diethylbarbiturate to the fermentation medium led to the sole production of rifamycin B6 which was obtained in crystalline form. Its structure has been determined by chemical7,and X-ray analysis9. The rifamycins might easily have excaped detection altogether, since rifamycin B has no antibacterial activity. However, it is spontaneously oxidized to rifamycin 0 and hydrolyzed to rifamycin S, a naphthoquinone derivative reduction yields the naphthohydroquinone derivative rifamycin SV (Fig. 4). These compounds inhibit the growth of Gram-positive bacteria at concentration as low as 0.0025 jug/ml. 

The structure of the ansamycins determines not only their activity on RNA polymerase, but also other important characteristics such as their ability to penetrate into bacteria and their pharmacokinetics and absorption in the host. To cite just a few examples rifamycin B, containing a free carboxylic acid group, has no antibacterial activity, although it inhibits RNA polymerase as strongly as rifampicin. Damavaricin C behaves similarly to rifamycin B, whereas its 6-methyl ether inhibits RNA polymerase to a lesser extent, but has good antibacterial activity23. Rifampicin owes its widespread clinical use to the fact that, in contrast to most other rifamycin derivatives, it is well absorbed when given orally. 

Rifamycin SV is a semi-synthetic antibiotic derived from rifamycin B, a substance produced during growth of certain strains of Streptomyces mediterranei. 

Rifamycin SV (rINN), a semisynthetic macrocyclic antibiotic derived from natural rifamycin B, has been used in the therapy of tuberculosis and in some European countries as a topical antibiotic. Anaphylaxis has been reported after systemic administration, and rarely after topical application. 

Rifabutin, U5P. Rifabutin, the spiroimidazopiperidyl derivative of rifamycin B was approved in the United States for the prophylaxis of disseminated MAC in AIDS patients on the strength of clinical trials establishing its effectiveness. The activity of rifabutin against MAC organisms greatly ex-... 

Efficient incorporation of [4 - H, (/- Clphenylalanine into deoxaphomin (149) without change in ratio indicates that this amino-acid is an intact precursor for (149) as it is for the other cytochalasins. More importantly radioactive deoxaphomin obtained in this way was used to see if it was a precursor for cytochalasin B (147). A highly efficient incorporation was obtained and without change in isotope ratio thus establishing that cytochalasin B (147) is derived from (149) manifestly by introduction of an oxygen atom between C-9 and C-23. A similar oxygenation has been observed in the in vivo transformation of rifamycin W to rifamycin B. 

Rifampin is used as an antibiotic. It is a semisynthetic derivative of rifamycin B, a macrocyclic antibiotic produced by the mold Streptomyces mediterranei. 

Evidence for the initial steps of rifamycin B biosynthesis can be seen in the accumulation of a tetraketide chain elongation intermediate P8/1-0 58 from a mutant of A. mediterranei [92]. This evidence and the demonstration from feeding experiments that the carbons on either side of the ether link in the ansa bridge derive from the same propionate unit [93] indicate that this ether moiety is formed after the initial biosynthesis of a fully extended polyketide chain. 

The biological activity of rifamycins has been described [179b]. Rifamycin S (102) results from the oxidation of rifamycin B (98) to rifamycin O (101) and final hydrolysis, and rifamycin SV (103) is given by reduction of rifamycin S (98) to the corresponding hydroquinone. The biological activity is retained by all compounds. Rifampicin, a hydrazone derivative of 3-formyl rifamycin SV, is a widely used orally active tuberculostatic agent [182]. 

Unusual features in this pattern for rifamycin S biosynthesis are loss of the propionate-derived methyl group from C-28 and insertion of oxygen between C-12 and C-29 of a precursor (195). Important support for the correctness of these conclusions comes from the isolation, from a N. mediterranei mutant, of rifamycin W (196), which possesses the unmodified skeleton (195) and whose biosynthesis accords with that illustrated in (195). " Moreover, rifamycin W (196) was found to be converted by a rifamycin B-producing strain of N. mediterranei into rifamycin B [as (193), with oxygen-substituted hydroquinone ring b], and it may be therefore that rifamycin W is an important intermediate in the biosynthesis of rifamycins. 

Rifamycin B, produced by Amycolatopsis mediterranei, is one of the most notable members of the ansamycin family [36, 37, 64, 65] (Fig. 14). It has been used clinically in a synthetically modified form called rifampicin and it is still one of the first-line therapies effective in the treatment of tuberculosis and other mycobacterial infections. The starter unit for rifamycin polyketide assembly is part of the chromophore and is derived from 3-amino-5-hydroxybenzoic acid. Five polyketide synthases are involved in the formation of rifamycin chromophore and the first polyketide synthase contains at the N terminus the loading domain for 3-amino-5-hydroxybenzoic acid, which consists of an acyl-CoA ligase linked to ACP, and module 1-3. The rifamycin polyketide synthase lacks a TE domain at the C terminus. The release of polyketide chain from polyketide synthase and the formation of amide to generate the macrocyclic lactam will be catalyzed by RifF, which is very similar to arylamine A-acetyltransferase. 

The discovery of rifampicin in 1967 is considered one of the greatest achievements in the history of chemotherapy against tuberculosis. Rifampin was developed in the Lepetit Research Laboratories (Italy) as part of an extensive program of chemical modification of the rifamycins, the natural metabolites of Nocardia mediterranei. All of the studies leading to highly active derivatives were performed on a molecule (rifamycin B) that was itself practically inactive. Systematic structural modifications of most of the functional groups of the rifamycin molecule were... 

Rifamycins are microbial-derived macrolides that were isolated in 1957 from the actinomycete Streptomyces mediterranei, obtained from the soil of the pine forests of southern France [18]. Of these, rifamycin B (306) is the least toxic. Addition of diethylbarbituric acid to the fermentation medium results in the production of 306 only. Rifampicin is the C3-hydazone semisynthetic derivative of rifamycins. Rifamycins show in vitro and in vivo anti-poxyviruses, e.g., VV activities [18]. These activities are apparently due to inhibition of the early step of viral morphogenesis which affects the assembly of immature viral particles. The inhibitory activity of rifamycins on retroviruses is also reported [18]. Many natural and semisynthetic rifamycins inhibit the virion RNA-dependent DNA polymerase (RT) [18]. Rifamycin B (306) was reported active against murine sarcoma virus (MSV) due to its RT, focus formation and cell transformation inhibitory activities [18]. Rifamycin antibiotics also inhibit the RT of Rauuscher leukemia virus, preventing its leukomogenic activity [18]. 

Among others, the ansamycin antibiotics have displayed antibacterial, antitumor and herbicidal activities. For many years, rifampicin, a semisynthesized antibiotic derived from rifamycin B, has been utilized for the treatment of tuberculosis. 

An early aromatic ansamycin-precursor containing the seven-carbon amino starter unit and designated as P8/1-OG (72) was isolated from the non-rifamycin producing UV-mutants derived from the Nocardia mediterranei strain N813 (a rifamycin B producer) [118]. This compound does not possess an ansa moiety, and can be considered to be an early ansamycin-precursor. 

Because the C-8 phenolic hydroxy group and the C-8 carbon atom of rifamycins B (1), O (7) and S (2) were found to be derived from the... 

For example, the biosynthetic sequence and stereochemistry of the formation of rifamycin B (1) were the same as those of streptovaricin C (44), in spite of the occurrence of demethylation at the C-14 position (derived from a propionate unit) and the insertion of an oxygen atom between C-15 and C-16 in the former compound (Fig. 11). 

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