The nitrofurans are chemical compounds with antimicrobial synthetic broad spectrum. These are often used to control bacterial infections in animals that are raised for commercial interests.
At present there is a rigorous control of their use, since it has been shown that they are potentially carcinogenic and mutagenic for DNA inside human cells.
Graphic diagram of the chemical skeleton of nitrofural, an antibacterial compound (Source: Vaccinationist via Wikimedia Commons)
Its use as a preventive and therapeutic treatment in animals raised for food production and meat consumption has even been prohibited. The European Union controls and inspects the presence of nitrofuran-based antibiotics in meat, fish, shrimp, milk and eggs.
The first reports on the antibacterial action of nitrofurans and their derivatives date back to the 1940s. It was in 1944 when, due to their antimicrobial action, they began to be used intensively in the preparation of soaps, topicals, deodorants, antiseptics, etc.
Although there is a large body of written literature on nitrofurans and their derivatives, little is known about the mechanism of action of these compounds, although the metabolites of nitrofurans have been shown to be more toxic than the original compounds themselves..
Characteristics of nitrofurans
These compounds are characterized by a heterocyclic ring consisting of four carbon atoms and one oxygen; the substituents are an azomethine group (-CH = N-) that is attached to carbon 2 and a nitro group (NO2) that is attached to carbon 5.
Dodd and Stillmanl, in 1944, testing 42 furan derivatives, discovered that nitrofurazone (the first nitrofuran) contained the azomethine group (-CH = N-) as a side chain, this compound turned out to be highly effective as an antimicrobial chemical when applied in a topical.
Additionally, Dodd and Stillmanl claimed that none of the nitrofuran compounds were found in nature. Today it continues to be the case, all nitrofurans are synthesized synthetically in the laboratory.
Nitrofurans were originally defined as chemotherapeutic compounds, since they controlled bacterial infections and apparently did not "harm" the patient who ingested them.
Between 1944 and 1960, more than 450 compounds similar to nitrofurazone were synthesized and studied to determine their antimicrobial properties, but currently only six are used commercially, these are:
- Nitrofurazone
- Nifuroxime
- Guanofuracin hydrochloride
- Nitrofurantoin
- Furazolidone
- Panazona
Most of these compounds are poorly soluble in water and some are soluble only in acid solutions, through the formation of salts. However, they are all readily soluble in polyethylene glycols and in dimethylformamide.
Action mechanisms
The way in which nitrofurans act inside organisms is currently not well understood, although it has been suggested that their mechanism of action has to do with the breakdown of the nitrofuran ring.
This breaks down and separates within the medicated individuals. The branched nitro groups travel through the bloodstream and become embedded through covalent bonds in the tissues and cell walls of bacteria, fungi, and other pathogens.
Furthermore, as these compounds are rapidly metabolized within the body after ingestion, they form metabolites that bind to tissue proteins and create instability and weakness in the structure of the internal tissues of the patient and the pathogen.
Graphic diagram of the chemical skeleton of nifuratel, an antifungal compound (Source: Vaccinationist Via Wkimedia Commons)
The compounds and different derivatives of nitrofurans show a variable effectiveness in each species of bacteria, protozoan and fungus. However, at low concentrations most nitrofurans act as bacteriostatic compounds.
Despite being bacteriostatic, when the compounds are applied in slightly higher concentrations they become bactericidal. Some are even bactericidal in minimal inhibitory concentrations.
Nitrofurans have the ability to transfer in a residual way to secondary species, which was demonstrated through the following experiment:
Pig meat was treated with carbon 14 (C14) labeled nitrofurans. A group of rats were then fed such meat and, subsequently, it was found that about 41% of the total amount of nitrofurans labeled and administered to the meat were inside the rats.
Classification
Nitrofurans are typically classified into two classes: class A and class B.
Class A comprises the simpler nitrofurans represented by what is known as "formula I", where the R groups are alkyl, acyl, hydroxyalkyl or carboxyl groups, together with esters and certain derivatives.
Some compounds of class A or "formula I" are: nitrofuraldehydes and their diacetates, methylnitrofuryl ketone, nitrosilvan (5-nitro-2-methylfuran), nitrofurfuryl alcohol and its esters and other compounds with similar structure.
In class B are grouped derivatives of ordinary carbonyls such as semicarbazone, oxime and the more complex analogues that have been prepared to date within laboratories. These compounds are called "formula II".
Both classes have marked antimicrobial activity in vitro, but some members of class B have better in vivo activity than any of the compounds belonging to class A.
Nitrofuran metabolites
The pharmacological use of nitrofurans was prohibited by the European Union, since even though nitrofurans and their derivatives are rapidly assimilated by the metabolism of patients, they generate a series of stable metabolites that bind to tissues and are potentially toxic.
These metabolites are easily released due to the solubility of nitrofurans at acidic pHs.
Thus, the acid hydrolysis that occurs in the stomach of animals and patients treated with nitrofurans produces many reactive metabolites capable of covalently binding to tissue macromolecules, such as proteins, lipids, among others.
In all food-producing animals these metabolites have a very long half-life. When they are consumed as food, these metabolites can be released or, failing that, their side chains.
Rigorous tests are currently being carried out on foods of animal origin with high efficiency liquid chromatography (name derived from English High Performance Liquid Chromatography) to detect at least 5 of the metabolites of nitrofurans and their derivatives, these are:
- 3-amino-2-oxazolidinone
- 3-amino-5-methylmorpholino-2-oxazolidinone
- 1-aminohydantoin
- Semicarbazide
- 3,5-dinitrosalicylic acid hydrazide
All of these compounds released as metabolites of nitrofuran chemical reagents are potentially carcinogenic and mutagenic for DNA. Furthermore, these compounds can release their own metabolites during acid hydrolysis.
This implies that each compound is a potentially toxic metabolite for the individual after acid hydrolysis within the stomach.
References
- Cooper, KM, & Kennedy, DG (2005). Nitrofuran antibiotic metabolites detected at parts per million concentrations in retina of pigs-a new matrix for enhanced monitoring of nitrofuran abuse. Analyst, 130 (4), 466-468.
- EFSA Panel on Contaminants in the Food Chain (CONTAM). (2015). Scientific Opinion on nitrofurans and their metabolites in food. EFSA Journal, 13 (6), 4140.
- Hahn, FE (Ed.). (2012). Mechanism of action of antibacterial agents. Springer Science & Business Media.
- Herrlich, P., & Schweiger, M. (1976). Nitrofurans, a group of synthetic antibiotics, with a new mode of action: discrimination of specific messenger RNA classes. Proceedings of the National Academy of Sciences, 73 (10), 3386-3390.
- McCalla, DR (1979). Nitrofurans. In Mechanism of Action of Antibacterial Agents (pp. 176-213). Springer, Berlin, Heidelberg.
- Miura, K., & Reckendorf, HK (1967). 6 The Nitrofurans. In Progress in medicinal chemistry (Vol. 5, pp. 320-381). Elsevier.
- Olive, PL, & McCalla, DR (1975). Damage to mammalian cell DNA by nitrofurans. Cancer research, 35 (3), 781-784.
- Paul, HE, Ells, VR, Kopko, F., & Bender, RC (1959). Metabolic degradation of the nitrofurans. Journal of Medicinal Chemistry, 2 (5), 563-584.
- Vass, M., Hruska, K., & Franek, M. (2008). Nitrofuran antibiotics: a review on the application, prohibition and residual analysis. Veterinarni medicine, 53 (9), 469-500.