Rifamycin preparation

Venturini AP, Bertoli D, Marchi E Transcutaneous absorption of a topical rifamycin preparation Rifaximin (L/105). Drugs Exp Clin Res 1987 13 231-232. 

It was found that the macrocyclic ring of rifamycin was responsible for the complex formation of the antibiotic with E. coli RNA polymerase and for the inhibitory effect of the antibiotic on the enzyme. Changes in other parts of the molecule have little effect on the direct action on E. coli RNA polymerase but may affect its permeability characteristics . Some derivatives of rifamycin, prepared by substitution with cyclic secondary amines, displayed activity against rifampicin resistant mutants of Staphylococcus aureus . ... 

Rifamycins - Prom lunong the scores of semisynthetic rifamycins prepared from rifamycin SV (XV) and its 3-formyl derivative (XVI), Rifampicin (rifaldazine) (XVII)stands out as a dramatic chemotherapeutic improvement over the parent compound. ... 

Maggi, N., A. Vigevani, and R. Pallanza Desacetyl-Rifamycins Preparation and Antibacterial Properties. Experientia 24, 209 (1968). 

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

Rifaximin (4-deoxy-4/-methylpyrido[l, 2 -l,2]imidazo-[5,4-c]rifamycin SV, fig. 2) is a synthetic product designed to modify the parent compound, rifamycin, in order to achieve low GI absorption while retaining good antibacterial activity [37]. It is a rifamycin SV derivative, prepared by condensing 2-aminopyridine derivatives to 3-bromorifamycin S (fig. 3) [37-39]. This pyridoimidazo rifamycin SV derivative, which proved to be stable in gastric juice for 24 h, displays a zwitterionic nature at physiological pH [38]. 

Amino-terminated organosilanes were used to immobilize rifamycin B via its active carboxylic acid functionality leading to the formation of stable amide bonds between antibiotics and modified silica [7]. The organosilanes used were (3-aminopropyl)triethoxysilane or (3-aminopropyl)dimethylethoxysilane, and the procedure for preparation was as described in Section 2.2.1.1. Surface coverage data were not provided by the authors [7],... 

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. 

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 ... 

Since none of the compounds at the concentrations used showed a complete supression of splenomegaly, one would expect a residual viral activity in spleen extracts of mice, which received FLV suspensions preincubated with these compounds. Studies are now in progress to evaluate the leukemogenic activity of cell-free spleen extracts, prepared from mice inoculated with pretreated suspensions. Wu etal.63 have carried out such studies with RLV and rifamycin derivatives. They reported that the inoculation of mice with inocula from mice infected with RLV pretreated with AF-ABDP and AF/DNF1 did not cause splenomegaly. 

An example of the utilization of a bridged bicyclic ketone for preparation of an acyclic moiety is the stereoselective synthesis of the C-21 to C-27 segment of rifamycin-S, a member of the ansamycin family of antibiotics (Scheme 18). Rao et alP used ketone (61), derived from furan, to prepare lactone (62). Exhaustive reduction of (62) provided the segment (63), which contains five chiral centers of lifamycin-S. 

Dissolve 10 mg rifampicin (rifamycin SV) in 1.0 ml dimethyl sulfoxide. Prepare also a 5% (w/v) solution of trichloroacetic acid (TCA). 3-107. Place exactly 0.1 ml H-leucine solution (step 3-105) in a 125 ml Erlenmeyer flask and place the flask in the bath. 

Indeed, pent-l-enitols [225], glucal derivatives [226], and galactal and fucal analogs have all been obtained via l-en-3-ones by using the above-mentioned approach. Thermal cyclocondensation of aldehyde 117 with diene 118 gave racemic enone 119 (O Scheme 41), which is used as a s)uithon in the preparation of the rifamycin S chain [227]. 

Aryne cycloadditions to furans have been employed in the synthesis of bio-related molecules. For example, adduct 272 served as the starting point for the preparation of the aromatic segment of rifamycin W (an antibiotic). Previously unreported benzyne 274 (its precursor 273 was prepared in several steps from piperonal) readily gave cycloadduct 275 with furan, but unfortunately for a proposed route to podophyllotoxin, did not undergo... 

A large number of derivatives of the naturally occurring rifamycins have been prepared (30). 

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. 

Subsequently, 25-deacetyl-25-ep/-hydroxy-rifamycin S (8), an example of a rifamycin S epimer, was synthesized with the aim of increasing the intrinsic activity of rifamycin S (2). However, the biological evaluation did not confirm this hypothesis [57]. 23- p/-25-deacetylrifamycin S and 21-ep/-rifamycin S were also prepared [58, 59]. 

A semi-synthetic antibiotic, rifampicin (rifampin) (19), was prepared from compound 5, obtained by the formylation of the C-3 position of rifamycin SV (3), followed by the reaction of 5 with l-amino-4-methylpiperazine in tetrahydrofuran (Fig. 2) [69]. 

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