Quinoxaline antibiotics

Since many of the above-mentioned compounds possess major anti-infec-tious activity in addition to their role as growth promoters, their application in animal farming has already been discussed in previous chapters. Hence, this chapter concentrates on the remaining compounds within this group, namely the organic arsenicals, peptide antibiotics, quinoxaline-l,4-dioxides, and miscellaneous substances. 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Echinomycin (131) has been shown to be an antitumor agent and to have antiviral and antibacterial properties. Its structure elucidation represents a triumph for and mass spectral studies (75JA2497). It has been demonstrated that echinomycin functions by inhibiting RNA synthesis in organisms such as Staphylococcus aureus. Echinomycin, levomycin and actinoleutin are members of the quinoxaline-peptide antibiotic family and all contain one or more quinoxaline rings (67MI21402). 

Only a very few therapeutic agents, in marked contrast to the large number of entities that contain a pyrimidine ring, are based on the pyrazine ring. One of those, the anti-tubercular antibiotic pyrazinamide (68-6), probably acts by a similar mechanism as its pyridine parent, isoniazide. The tonnage chemical ort/zo-phenylene diamine (68-2) provides a convenient route to pyrazines. Thus condensation of that diamine with glyoxal (68-1) leads to quinoxaline (68-3). Treatment of the heterocycle with... 

Other heterocycles used as veterinary antibacterials are trimethoprim (43) (see below) and the quinoxaline iV,iV -dioxide, carbadox (39). Carbadox (39) is used as a feed additive, in which role it is effective against T. hyodysenteriae in the control of swine dysentery (annual sales for 1981 US 45 million). An in vitro comparison of the effectiveness of carbadox (39) with other antibiotics for the control of T. hyodysenteriae has been carried out (79MI10805). 

The majority of these are antibiotics and they cover a diverse group including the glycopeptide, avoparcin (95), tetracycline, macrolides, such as tylosin (23) and virginiamycin (96), as well as peptides, glycopeptides and terpenes. Antibacterials such as the quinoxaline-1,4-dioxide, carbadox (39), and nitrofurans, e.g. furazolidone (35) and nitrovin (97), are also represented. 

DCC is also used to prereact carboxyl groups with 0-benzylhydroxylamine prior to /8-lactam ring closure. A water soluble carbodiimide in combination with HOBt is used in several steps of the total synthesis of nisin, a pentacyclic polypeptide. Carbodiimides are also used for amide bond formation in the synthesis of the antiviral antibiotic distamycin Similarly, carbodiimides are used in the synthesis of a model depsipeptide lactone related to quinoxaline antibiotics. In the last synthesis, DCC in the presence of pyridine is used in the depsipeptide bond formation. 

Quinoxaline 1,4-dioxides possess antibacterial activity, " as well as being fungicides, insecticides, and herbicides. Quinoxaline-2-carboxylic acid 1,4-dioxide has been isolated from cultures of Sireplomyces ambrofaciens and this compound has been shown to have antibiotic properties. Echinomycin, from the quinoxaline-peptide antibiotic family, contains one or more quinoxaline rings and is an antitumor agent. Quinoxaline derivatives are also antagonists at the jV-methyl-D-aspartate (NMDA) receptor of the glycine modulatory site. Poly(phenylquinoxalines) are used as high temperature polymers. 

The main search for biologically active quinoxalines has centered around the preparation of quinoxaline iV-oxides. 3-Substituted 2-methylquinoxaline 1,4-dioxides with high antibacterial activity have been prepared (Chapter IV). Quinoxaline 2-sulfonamide has had sustained use as a coccidiostat for poultry (Chapter XI). A series of naturally occurring quinoxaline antibiotics, the quinomycins and triostins, are known, but their therapeutic index is low (Chapter IX). 

Quinoxaline Antibiotics Containing Quinoxaline-2-carboxylic Acid Residues. 148... 

Predictably there have been several attempts to prepare biologically active compounds by the synthesis of quinoxaline derivatives related in structure to the naturally occurring quinoxaline antibiotics. Thus a number of quinoxalinoyl derivatives of amino acids and dipeptides " have been prepared and also bisquinoxalinoyl derivatives of types 46 and 47. ... 

Blum, S., Fiedler, H. P., Groth, I., Kempter, C., Stephan, H, Nicholson, G, Metzger, J., and Jung, G. (1995) Biosynthetic capacities of Actinomycetes. 4 Echmoserine, a new member of the quinoxaline group, produced by Streptomyces tendae. J. Antibiot. 48,619-625. 

In summary, it has been demonstrated that a number of compounds have specific analytical requirements due either to extensive metabolism or the legal definitions of the marker residues to be used for detection of use. For the quinoxaline-type antibiotics, the question of the most appropriate marker of use remains unanswered at present. For ceftiofur, differences in legislation worldwide mean that analytical requirements differ from region to region. As with the quinoxalines, a question has been raised as to whether the generally accepted marker residue is the optimum. 

Until now, several types of polycyclic aromatic nitrogen heterocycles have been known. In fact, heterocyclic synthesis plays an important role in modern life. Among the nitrogen heterocycles, quinoxaline and phenazine derivatives have attracted great interest because of their wide application in organic and medicinal chemistry. Many phenazine compounds are found in nature and are produced by bacteria. Quinoxalines are the fundamental components of several pharmacological active compounds and some antibiotics such as levomycin, echinomycin, and actinomycin (Bailly et al, 1999 Dell et al, 1975). 

Glund K, Schlumbohm W, Bapat M, Keller U. Biosynthesis of quinoxaline antibiotics Purification and characterization of the quinoxaline-2-carboxylic acid activating enzyme from Streptomyces niosrmMS. Biochem 1990 29 3522-3527. 

Inhibitors of bacterial DNA synthesis These can have a broad spectrum of activity, have a low molecular weight (about 250) and require withdrawal periods. Nitrofurans and quinoxaline-M-oxides fall into this category of antibiotics. 

Quinoxaline moiety possesses several biological activities such as antitumor [104], antimycobacterial [105], antidepressant [106], etc. Some antibiotics, such as levo-mycin, actinolentin, and echinomycin, also contain a quinoxaline scaffold. 

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