Carboxin is a narrow-spectrum fungicide used as a

seed treatment A seed treatment is a treatment of the seed with either chemical agents or biological or by physical methods. Usually done to provide protection to the seed and improve the establishment of healthy crops. Not to be confused with a seed coating. ...

in agriculture to protect crops from fungal diseases. It was first marketed by

Uniroyal Uniroyal, formerly known as the United States Rubber Company, is an American manufacturer of tires and other synthetic rubber-related products, as well as variety of items for military use, such as ammunition, explosives, chemical weapons and op ...

in 1969 using their brand name Vitavax. The compound is a benzanilide

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

that combines a

heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

acid with

aniline Aniline (From , meaning ' indigo shrub', and ''-ine'' indicating a derived substance) is an organic compound with the formula . Consisting of a phenyl group () attached to an amino group (), aniline is the simplest aromatic amine. It is an in ...

to give an inhibitor of

succinate dehydrogenase Succinate dehydrogenase (SDH) or succinate-coenzyme Q reductase (SQR) or respiratory complex II is an enzyme complex, found in many bacterial cells and in the inner mitochondrial membrane of eukaryotes. It is the only enzyme that participates ...

(SDHI).

Synthesis

The first synthesis of carboxin was disclosed in patents filed by Uniroyal. : Carboxin synthesis

Ethyl 2-chloroacetoacetate is treated with

2-mercaptoethanol 2-Mercaptoethanol (also β-mercaptoethanol, BME, 2BME, 2-ME or β-met) is the chemical compound with the chemical formula, formula HOCH2CH2SH. ME or βME, as it is commonly abbreviated, is used to reduce disulfide bonds and can act as a biological ...

and base, followed by cyclisation and water removal under acidic conditions. The resultant ethyl ester of the 1,4-oxathiine

heterocycle A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...

is then formed into an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

with aniline using standard conditions via the

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

and acid chloride. This gives carboxin in high overall yield. The compound has been crystallised in two polymorphic forms, which have equal biological activity.

Mechanism of action

The mechanism of action of carboxin was not established until several years after it was first reported in 1966. In the period 1971–1975, evidence grew that it acted by inhibition of

(SDHI), and later work showed that it binds to the quinone reduction site of the enzyme complex, preventing

ubiquinone Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...

from doing so. As a consequence, the

tricarboxylic acid cycle The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions that release the energy stored in nutrients through acetyl-CoA oxidation. The e ...

and

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

cannot function. The compound was an early example of a fungicide exhibiting systemic movement from its application site on the crop plant to protect newly-growing tissue.

Usage

Owing to its systemic properties, carboxin is suitable for use as a

to give fungal control on the growing crop. However, it controls a relatively narrow range of species: mainly '' Tilletia spp.'' (known as bunts and smuts) in cereal crops and

Rhizoctonia ''Rhizoctonia'' is a genus of fungi in the family Ceratobasidiaceae. Species form thin, effused, corticioid basidiocarps (fruit bodies), but are most frequently found in their sterile, anamorph state. ''Rhizoctonia'' species are saprotrophic, ...

in cotton and vegetables. The compound was used in Australia, the EU, the UK and the US but registration has lapsed in the EU. It was reported to have had a total worldwide sales of $75 million in 2014.

Human safety

Carboxin has low mammalian toxicity and is not persistent in the environment. One of its

metabolites In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

, the

sulfone In organic chemistry, a sulfone is a organosulfur compound containing a sulfonyl () functional group attached to two carbon atoms. The central hexavalent sulfur atom is double-bonded to each of two oxygen atoms and has a single bond to each of ...

, is also active as an SDHI and has been sold as the fungicide oxycarboxin.

Analogues

Carboxin was the first SDHI-type fungicide and its invention triggered a search for compounds with improved properties, particularly for

active ingredients An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. ...

which would control a broader range of economically-important diseases.

Boscalid Boscalid is a broad spectrum fungicide used in agriculture to protect crops from fungal diseases. It was first marketed by BASF in 2002 using their brand name Endura. The compound is an biphenyl amide derived inhibitor of succinate dehydrogenase. ...

, introduced in 2003, retained the aniline amide part-structure but with a

pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...

ring in place of the 1,4-oxathiine and with a second

benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...

ring attached to the aniline portion. By 2014, it had annual sales of $390 million. , over 18 related amides had been marketed, with seven of these being derivatives of 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid. The Fungicides Resistance Action Committee (FRAC) assigns fungicides into classes so as to facilitate resistance management and SDHI form one group.

Brands

Carboxin is the

ISO The International Organization for Standardization (ISO ; ; ) is an independent, non-governmental, international standard development organization composed of representatives from the national standards organizations of member countries. Me ...

common name In biology, a common name of a taxon or organism (also known as a vernacular name, English name, colloquial name, country name, popular name, or farmer's name) is a name that is based on the normal language of everyday life; and is often con ...

for the active ingredient which is formulated into the branded product sold to end-users. Vitavax is the brand name originally used by Uniroyal but as the compound's patents expired it became available to many other manufacturers and has been sold under multiple names.

References

{{reflist Fungicides Anilides Heterocyclic compounds with 1 ring