Rifamycins semisynthetic

Antituberculin Agents. Rifampin [13292-46-17, a semisynthetic derivative of rifamycin SV, is a most valuable dmg for treatment of tuberculosis, an infection caused by mycobacteria, leprosy, and an expanding range of other infections (23). Cycloserine [64-41-7] has been used to a limited extent for treatment of tuberculosis as a reserve dmg. Although cycloserine inhibits bacteria by interfering with their cell wall biosynthesis, it has toxic side effects in humans in the form of neurotoxicity. Capreomycin [11003-38-6] and to a much lesser extent viomycin [32988-50-4] both of which are peptides, have also been used for treatment of this disease. 

Marchi E, Montecchi L, Venturini AP, Mascel-lani G, Brufani M, Cellai L 4-Deoxypyri-do[l, 2 l,2]imidazo[5,4-c]rifamycin SV derivatives. A new series of semisynthetic rifamycins with high antibacterial activity and low gastroenteric absorption. J Med Chem 1985 28 960-963. 

Marchi E, Mascellani G, Montecchi L, Brufani M, Cellai L L/105, a new semisynthetic derivative of rifamycin SV, synthesis and structure-activity relationship. Chemioterapia 1983 2 38. 

Rifaximin, a virtually nonabsorbed antibiotic, is a semisynthetic rifamycin derivative, with a broad antimicrobial spectrum that includes most Gram-positive and Gram-negative bacteria, both aerobes and anaerobes [1, 2], Unlike systemically available antibiotics, this antimicrobial allows localized targeting (e.g. enteric or cutaneous) of pathogens and is associated with a minimal risk of systemic toxicity or side effects [3, 4], Provided that nonabsorbed antibiotics are as effective as systemically absorbed drugs for the target illness, their safety and toler-... 

Rifamycin SV (133, Fig. 23) is a naturally occurring macrocycle isolated from Nocardia mediterranei by Senti, Greco and Ballotta in 1959. It shows a high in vitro antibiotic activity through inhibition of DNA-dependent RNA polymerase, but bioavailability is low due to its poor water solubility. The semisynthetic derivative rifampicin (135) displays markedly higher water solubility and in vivo activity. We chose 3-formylrifamycin (134) as model macrocycle for the possibility of binding it to solid phase by hydrazone bond formation in a manner similar to rifampicin (Fig. 24). 

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

Pharmacology Rifabutin, an antimycobacterial agent, is a semisynthetic ansamycin antibiotic derived from rifamycin S. It is not known whether rifabutin inhibits DNA-dependent RNA polymerase in Mycobacterium avium or in Mycobacterium... 

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. 

The rifamycins, a class of antibacterials isolated from Streptomyces mediterranei, contain a macrocyclic ring bridging across two nonadjacent positions on an aromatic system. Rifampicin (9.96), a semisynthetic derivative of rifamycin, is a drug of choice in the treatment of tuberculosis as well as leprosy, either alone or in combination with other drugs. Rifampicin is much safer than other antituberculotics since it inhibits DNA-directed RNA polymerase in bacteria but not in mammals. Another rifamycin, rifabutin (9.97), is a spiroimidazopiperidyl derivative of the rifamycin. 

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at... 

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. 

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

Many antibiotics are highly specific inhibitors of biological processes. Rifampicin and actinomycin are two antibiotics that inhibit transcription, although in quite different ways. Rifampicin is a semisynthetic derivative of rifamycins, which are derived from a strain of Streptomyces. 

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. 

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

Rifampicin (Fig. 10.70) is a semisynthetic rifamycin made from rifamycin B—an antibiotic isolated from Streptomyces mediterranei. It inhibits Gram-positive bacteria and works by binding non-covalently to RNA polymerase and inhibiting RNA synthesis. The DNA-dependent RNA polymerases in eukaryotic cells are unaffected, since the drug binds to a peptide chain not present in the mammalian RNA polymerase. It is therefore highly selective. 

If a drug fails to meet present day standards because of low in vitro potency, metabolic, or chemical instability, poor oral absorption or high degree of serum and tissue binding, experience teaches that the prospects for improvement via structural modification are good—if systematic structural modification with retention of biological activity is feasible. The clinically established semisynthetic cephalosporins, rifamycin SV and rifampicin represent precisely this kind of improvement, while laboratory data indicate that it has also been achieved in the coumermycin series as well (96, 97). 

Semisynthetic Rifamycins. The degree and variety of the improvements that can be made in an antibiotic that has no clinical utility per se are well illustrated by the semisynthetic rifamycins (Figure 22) (102). The microbial metabolite, rifamycin B, is unstable in aqueous solutions exposed to oxygen and owes most, if not all, of its apparent activity to the corresponding 1,4-quinone, rifamycin S. Reduction of this quinone... 

The rifamycins (rifampin, rifabutin, rifapentine) are related macrocyclic antibiotics produced by Amy-colatopsis mediterrane rifampin (rifadin rimactane) is a semisynthetic derivative of rifamycm B. 

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]. 

Rifamycins S (2) and SV (3) were first obtained by the transformation of 1, and these antibiotics were also isolated from the fermentation broth of Micromonospora lacustris sp. nova, or its mutant, together with 3-thiomethylrifamycin SV (4) [43,44]. Rifamycin B (1) seemed to be formed from rifamycin S (SV) (2 (3)) by the addition of a Cs-precursor as the glycolic acid moiety [45]. As the synthetic precursor of the semisynthetic ansamycin antibiotics, 3-formylrifamycin SV (5) was prepared from rifamycin SV (3), as discussed in the following section. 

Other examples of naphthalenoid ansamycin antibiotics with a sulphur atom are CP-50833 (28), obtained from the culture broth of Streptomyces nigellus subsp. africanus ATCC31496 [80], and the semisynthetic antibiotics derived from rifamycin S (2), i.e., 3-thiomethylrifamycin S and 3-thiomethylrifamycin SV (4) which were obtained by repeatedly treating rifamycin S with MeSH [81]. The double bond at the C4-C5 position of 28... 

In this section, a semisynthetic antibiotic rifampicin, which plays an important role as a chemotherapeutic agent against tuberculosis, and its starting material rifamycin SV and related compounds are described. 

Rifamycins B and O can be transformed into rifamycin S, and rifamycin SV is obtained by treating rifamycin S with ascorbic acid [5]. Formylation of the C3 position of rifamycin SV, followed by the combination of this alkaloid with l-amino-4-methylpiperazine, gave the semisynthetic ansamy-cin rifampicin. Rifampicin was prepared in 1966, and it is one of the most effective antituberculosis agents at present. The chemical structures of the rifamycins were finally clarified in 1973-1974 [6,7]. 

Rifamycin B (D 4) Inhibition of RNA synthesis, in medicine less toxic semisynthetic derivatives are used... 

Fig. 6.3 Structures of rifamydn SV, a rifamycin B structure, and starting point for rifampicin which has a 4-methyl-l-piperazinaminyl side chain. The semisynthetic rifapentine is also used cUnicaUy...

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