2- Nitrofuran

The nitrofurans encompass a class of synthetic antibacterials characterized by the 5-nitro-2-furanyl group  

With relatively few exceptions, the R function contains the azomethine (—CH=N—) moiety. The most prominent exceptions contain the olefinic 

Kirk-Othmer Encyclopedia of Chemical Technology (4th Edition) 

The antimicrobial activity of this class of compounds was first reported ia 1943 (1) and this finding was described iadependendy four years later (2). After iavestigation of several derivatives, it was concluded that the 5-nitro function was responsible for the observed antimicrobial activity (3). These preliminary findings focused attention on this area of research and as a result, several thousand nitrofurans have been prepared, and thousands of articles have been prepared, and thousands of articles have been pubUshed describiag the extensive efforts ia these areas. 

Although in vitro mutagenicity tests suggest that some nitrofurans in general provoke a positive response, use of in vivo mammalian systems has produced equivocal or negative results. 

The nitrofurans are synthetic antibacterial compounds, all containing in their molecule a characteristic 5-nitrofuran ring (Fig. 3.5). Furazolidone, nitrofurazone, furaltadone, and nitrofurantoin are all nitrofiirans that have been widely used in the prophylactic and therapeutic treatment of infections caused by bacteria and protozoa in swine, cattle, poultry, rabbits, and fish. They have been also used as feed additives in animal husbandry. They are very effective drugs and do not appreciably contribute to the development of resistance (120). 

Nitrofurans are metabolized in vivo to reduced forms responsible for the effects exerted upon bacteria. These metabolites inhibit bacterial respiration, glucose metabolism, and ribosomal function, and may damage bacterial DNA. 

Furazolidone has been used for treatment of Salmonella infections in most farm animals. It has been also used as a feed additive for growth-promoting purposes. For poultry it was given in the feed at a level of 0.04% for 10 days, and in large animals at an oral dosage of 10-12 mg/kg bw for 5-7 days. 

Furazolidone is extensively metabolized in animals after its absorption from the gastrointestinal tract (125). Immediately after its last administration to chickens and pigs, residual concentrations of the parent drug in muscle, kidney, and liver tissues were less than 0.5 ppb (126). In chicken and swine urine, the unchanged furazolidone occurred only in trace amounts, but a large number of metabolites, most of which could not be identified, appeared. Among those metabolites, the open-chain cyano metabolite, 3-(4-cyano-2-oxobutylideneamino)-2-oxazolidone, was most common in animal species. 

In trout species held at 8-14 C and given medicated feed at the 35 ppm level for 20 days, residues of the parent compound accumulated in muscle during the medication period, reaching a maximum of 0.482 ppm at day 10 of medication (131). After withdrawal of the medication, residues fell rapidly to less than 0.075 ppm at day 10 posttreatment. 

Several nitrofurans have been marketed either regionally or woddwide in the human and veterinary areas because of their broad spectrum of activity, relatively mild toxicity, and low tendency for resistance development. However, accurate total volumes or sales of these products on a global basis are not generally available. In the United States, nearly four million prescriptions were written in 1989 for products containing nitrofiirazone or nitrofurantoin. U.S. sales during this period for these products approached 70 miUion thus therapy with this class of compoimds remains a significant therapeutic alternative. 

Furans are five-membered ring heterocycles, and it is the presence of a nitro group in the 5 position of the furan ring that confers antibacterial activity on many 2-substituted furans. Although the use of nitrofurans in food-producing species is prohibited because of their carcinogenicity, nitrofurantoin, nitrofurazone, furazolidone, and nifuroxazide are used in small animals and horses. 

The mechanism of antibacterial action of the furan derivatives is unknown. However, the reduced forms of nitrofurans are highly reactive and are thought to inhibit many bacterial enzyme systems, including the oxidative decarboxylation of pyruvate to acetylcoenzyme A. Nitrofurans (see list in Table 1.7) are bacteriostatic but, at high concentrations, can be bactericidal to sensitive organisms. Both chromosomal and plasmid-mediated mechanisms of resistance to nitrofurantoin occur, and these most commonly involve the inhibition of nitrofuran reductase. 

Furazolidone is occasionally used in small animals to treat enteric infections. It has activity against Giardia, Vibrio cholera. Trichomonas, coccidia, and many strains of Escherichi coli, Enterobacter, Campylobacter, Salmonella, and Shigella. Another nitrofuran, nifuroxazide, is used for treating acute bacterial enteritis. 

There is a paucity of information describing nitrofurans in the environment. This may reflect the fact that the 

Furazolidone 3- [(5-Nitro-2-furyl)methylene]amino -l,3-oxazolidin-2- 

The first drugs in this class to be introduced into clinical practice are simple derivatives of 5-nitrofurfural (18). Thus, the oxime is known as nitrofuroxime (19) while the semicarbazone is called nitrofurazone (20). In order to maintain better control over the distribution and metabolism of these antibacterial agents, increasingly complex side chains and rings have been grafted onto the hydrazone. 

in one such example, hydroxyethylhydrazine (21) is first converted to the carbamate (22). Condensation with 18 yields nidroxyzone (23) 

Cyclization of 21 by means of diethyl carbonate gives the corresponding aminooxazolidone (24). This compound is then condensed with benzaldehyde to Shiff base (25). An exchange reac- 

In a scheme intended to produce a more highly substituted oxazolidone, epichlorohydrin is condensed with morpholine in the presence of strong base to give the aminoepoxide, 27. Ring opening of the oxirane by means of hydrazine gives the hydroxy-hydrazine (28). Ring closure with diethyl carbonate leads to the substituted oxazolidone (29). Condensation with 18 affords furaltadone (30).  

31 (obtained by ring opening of the thiomethyl epoxide with hydrazine), with diethyl carbonate gives the oxazolidone, 32. Condensation with the ubiquitous 18 leads to nitrofuratel (33).  

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ANTIBACTERIALAGENTSSYNTTiETIC - NITROFURANS] (Vol2) 3-[(5-Nitro-2-furanyl)methyleneamino]-2-oxazolidinone... 

Alkylfurans, halofurans, alkoxyfurans, furfuryl ester and ethers, and furfural diacetate [613-75-2] behave similarly. Furans containing electron withdrawing constituents, for example, furfural, 2-furoic acid, and nitrofurans, fail as dienes even with very strong dienophiles. 

Chemically synthesized antimicrobials used in animal and poultry feeds include arsenicals, eg, arsanilic acid [98-50-0] sodium arsanilate [127-85-5] and roxarsone [121-19-7]-, sulfa dmgs, eg, sulfadimethoxine [122-11-2], sulfamethazine [57-68-1], and sulfathiazole [72-14-0]-, carbadox [6804-07-5]-, and nitrofurans, eg, furazoHdone [67 5-8] and nitrofurazone [59-87-0] (see Antibacterial agents, synthetic Antiparasitic agents). 

These three nitrofurans have been used therapeutically for over 30 years with no reports of human neoplasia and the relevance of the animal findings to short term therapy in humans has not been estabUshed. 

Most commerciali2ed nitrofurans are derived from 5-nitro-2-furancarboxaldehyde [698-63-5] or the corresponding diacetate. 

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