Rifamycin SV derivatives

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]. 

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. 

Cellai L, Cerrini S, Segre A, Battistoni C, Cossu G, Mattogno G, Brufani M, Marchi E A study of structure-activity relationships in 4-deoxypy-rido[l, 2 -l,2]imidazo[5,4-c]rifamycin SV derivatives by electron spectroscopy for chemical analysis and HNMR. Mol Pharmacol 1985 27 103-108. 

This mechanism of Inhibition, however, was observed at one hundred times higher levels, with the structurally divergent antibiotic streptoly-digin l and indications for an alternate or additional mechanism have been noted in inhibition studies of rifampin-resistant bacteria with semisynthetic rifamycin SV derivatives ... 

Gurgo, C., D. P. Grandgenett, G. F. Gerard, and M. Green Interaction of Purified Ribonucleic Acid Directed Deoxyribonucleic Acid Polymerase of Avian Myeloblastosis Virus and Murine Sarcoma-Leukemia Virus with a Rifamycin SV Derivative. Biochem. 13, 708 (1974). 

Moss, B. Ansamycins (A) Rifamycin SV Derivatives. In W. A. Carter (Edit.), Selective Inhibitors of Viral Functions, p. 313. Cleveland CRC Press, Inc. 1973. 

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. 

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). 

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. 

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). 

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. 

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 ... 

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. 

Rifamycins — Systematic chemical modification of rifamycin SV (XXI) has led to remarkable chemotherapeutic improvements which include broadening the antimicrobial spectrum to include gram-negative bacteria, gaining oral activity and obtaining higher stability. Such a derivative is exemplified by rifaldazine (XXII)which has shown clinical promise in the treatment of respiratory and urinary-tract infections, osteomyelitis and tuberculosis. 

Mannich bases (XXIII)of rifamycin SV and rifazine, a phenazine derivative of rifamycin SV, are other examples of enhanced therapeutic efficacy through structural changes in the natural product. 

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]. 

The rifamycins are antibiotics isolated in Italy from Streptomyces mediterranei and then chemically altered to give more selective products. Rifamycin SV 4.37a) is the original substance but its derivative rifampicin (rifampin in the USA) 4.37b) is now the established drug in this series. It is much used, in conjunction with isoniazid (Section 11.9), for the cure of severe cases of tuberculosis but is still too expensive for general use (American Thoracic Society, 1980). Because it is one of the most selective of all known anti-bacterial drugs, it could profitably... 

When cultures of rifamycin S—producing mutants are prolonged beyond the maximum production yields, several transformation products are formed, namely, rifamycin R and the thiazorifamycins P, Q, and Verde (Figure 8). Rifamycin R results from hydroxyla-tion of methyl 30 of rifamycin SV and, thus, is 30-hydroxyrifamycin SV (57). The thiazorifamycins derive from condensation of cysteine with rifemycin S, with formation of an unstable ihiazinorifamycin that spontaneously rearranges into the thiazorifamycins (58,59). 

In a few countries, the same indications were covered by a different derivative, namely, the diethylamide of rifamycin B (rifamide) prepared by condensing rifamycin B with diechylamine in the presence of dicyclohexylcarboditmide. Rifamide has biolc ical properties very similar to those of rifamycin SV... 

Recently, the association of amino acids and some other low-molecular weight compounds with rifamycin SV in water was studied by H NMR titrations. Rifamycin binds aromatic amino acids with pronounced enantioselectivity in favor of L-enantiomers and forms complexes with heterocyclic compounds but does not interact with aliphatic amino acids and with simple benzene derivatives. The binding constants for several guests are given in Figure 12. 

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