Of rifamycinS

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. 

Difficulties encountered in the separation and stabihty of the individual rifamycins led to studies to increase the yield of individual components of the complex. The addition of sodium diethylbarbitutate to the fermentation medium of N. mediterranei resulted in the formation of rifamycin B as practically the only substance formed (91,92). 

Chemical Properties and Derivatives, There have been thousands of rifamycin derivatives prepared in an attempt to obtain a broader... 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Scheme 8.29 Kishi s approach for the construction of the C19-C26 polyketide-type segment of rifamycin S.

Figure 3.6 Comparison of the chemical structures of rifamycin (Rifampicin ) and rifamycin CGP 4832 the latter is transported by FhuA. Note the entirely different chemical structures (Figure 3.2) and conformations (Figure 3.5) of the ferrichrome and albomycin FhuA transport substrates.

K., Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver, Hepatology... 

In order to overcome the limitations of the above drugs, a series of rifamycin derivatives with improved pharmacokinetic (i.e. virtually absence of GI absorption) and pharmacodynamic (i.e. with broad spectrum of antibacterial activity) properties have been synthesized at Alfa Wassermann laboratories [33]. Amongst the different molecules, the compound marked L-105 and later... 

Fig. 3. Stepwise synthesis of rifaximin (from De Angelis [39]). The reaction of rifamycin S (I) with pyridine perbro-mide (II) in 2-propanol/chloroform (70/30) mixture at 0°C gives 3-bromorifamycin S (III), which is then condensed with 2-amino-4-methyl-pyridine (IV) at 10°C. The o-quinonimic compound (V) is then obtained. This compound is finally reduced with ascorbic acid to rifaximin. 

Lancini GC, Sartori G Rifamycins LXI In vivo inhibition of RNA synthesis of rifamycins. Experientia 1968,24 1105-1106. 

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 nonabsorbable derivative of rifamycin, has shown promising bactericidal action against both aerobes and anaerobes, such as bacterioides, lactobacilli and clostridia [33, 34], The development of resistance to this antibiotic can occur, but resistant strains rapidly disappear from the intestine thus allowing cyclic administration of rifaximin. Controlled clinical trials showed efficacy of rifaximin in adult and pediatric patients with infectious diarrhea [36,37], hepatic encephalopathy [38], post-surgical complications [39] and colonic diverticulosis [40], Only recently was the efficacy of rifaximin in the treatment of SIBO demonstrated [41-43]. 

Among the syntheses of complicated natural products, the total synthesis of rifamycin S (44) is another example that shows how a complicated structure can be constructed by applying the concept of double asymmetric synthesis (see Section 1.5.3 for double asymmetric synthesis). Rifamycin S is one of the an-samycin antibiotics, characterized by a distinct structural feature a macro-... 

The total synthesis of rifamycin S was one of Kishi s many achievements in organic synthesis.6 Kishi recognized that a certain type of (Z)-olefin such as 51 tends to take a conformation in which C-l, C-2, C-3, and H-3 are nearly co-... 

In the application of the above discovery, ( )-3-benzyloxy-2-methyl pro-pionaldehyde 52 is used as the starting material in the synthesis of rifamycin A. As outlined in Scheme 7-12, compound 52 is converted to allyic alcohol 55 via a series of chemical reactions. Epoxidation of 55 proceeded stereoselectively, giving a single epoxide that affords 57 after subsequent treatment. Compound 57 may be converted to 58 upon acetonide formation. 

Further transformation of 62 to the ansa chain (+ )-66 is briefly summarized in Scheme 7-14 without a detailed discussion. Compound ( )-66 has now been properly functionalized for coupling with the aromatic unit of rifamycin. 

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

Stereoselective addition of cuprates to y-alkoxy enoates of type 49 [17] (see Schemes 6.8 and 6.9) has been used in the construction of polypropionate-type structures. Thus, a sequence of diastereoselective cuprate addition, enolate formation, and diastereoselective oxygenation with Davis s reagent has been applied iteratively to provide a C19-C28 segment of Rifamycin S (60) [17c, d]. 

Rifamycin S Scheme 6.9. Construction of the polypropionate segment of Rifamycin S through iterative diastereoselective cuprate addition to acyclic enoates. a) Me2CuLi, TMSCI,... 

In the case at hand, the y-alkoxy-a, j6-unsaturated esters 13, 15, 17, and 19 were treated with lithium dimethylcuprate in the presence of excess TMSCl in THF at —78 °C, producing the adducts 14, 16, 18, and 20 in 95, 85, 83, and 86% yields, respectively (Scheme 9.4). It was thus possible to assemble the acyclic C19-C28 subunit 21 of rifamycin S (12), which represents the longest sequence of contiguous propionate-derived units among the macrolides and ansa antibiotics. The strategy has also successfully been applied to the syntheses of the (all propionate)-derived segments of such natural products as bafilomycin Ai [13], hygrolidin [14], elaiophylin [15], and scytophycin C [16]. 

Lounis N, Roscigno G. (2004) In vitro and in vivo activities of rifamycin derivatives against mycobacterial infections. Curr Pharm Des 10 3229-3238. 

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

Uses Travelers D (noninvasive strains of E. coli) in pts >12 y Action Not absorbed, derivative of rifamycin. Dose 1 tab PO daily x 3 d Caution [C, /-] Hx aUergy pseudomembranous cohtis Contra AUergy to rifamycins Disp Tabs SE Flatulence, HA, abd pain, GI distress, fevCT Interactions None significant EMS Monitor ECG and BP for signs of hypovolemia and electrolyte disturbances d/t D used primarily for D caused by contaminated food while traveling OD Sxs unknown symptomatic and supportive... 

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. 

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