{{Short description|Chemical compound used to kill fungi}} {{chembox |ImageFile = Carboxin.svg |PIN = 2-methyl-N-phenyl-5,6-dihydro-1,4-oxathiine-3-carboxamide |OtherNames = |Section1 ={{Chembox Identifiers |CASNo_Ref = {{cascite|correct|CAS}} |CASNo= 5234-68-4 |Beilstein = 983249 |ChEBI_Ref = {{ebicite|correct|EBI}} |ChEBI = 3405 |ChEMBL_Ref = {{ebicite|correct|EMBL}} |ChEMBL = 1231667 |ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |ChemSpiderID = 20027 |EC_number = 226-031-1 |PubChem= 21307 |KEGG_Ref = {{keggcite|correct|kegg}} |KEGG = |UNII = 5A8K850HDE |StdInChI_Ref = {{stdinchicite|correct|chemspider}} |StdInChI = 1S/C12H13NO2S/c1-9-11(16-8-7-15-9)12(14)13-10-5-3-2-4-6-10/h2-6H,7-8H2,1H3,(H,13,14) |StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |StdInChIKey = GYSSRZJIHXQEHQ-UHFFFAOYSA-N |SMILES = CC1=C(SCCO1)C(=O)NC2=CC=CC=C2 }} |Section2={{Chembox Properties |Properties_ref =<ref name=PPDB>{{cite web |url=http://sitem.herts.ac.uk/aeru/ppdb/en/Reports/122.htm |title=Carboxin |publisher=University of Hertfordshire |author=Pesticide Properties Database |date=2023-07-21 |access-date=2023-08-03 }}</ref> |C=12 |H=13 |N=1 |O=2 |S=1 |MolarMass= 235.3 |Appearance= Off-white solid |Density= 1.45 g/cm<sup>3</sup> |MeltingPt= 91.5°C |Solubility= 134 mg/L |LogP= 2.3 }} |Section3={{Chembox Hazards |GHS_ref = <ref>{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/compound/56933411#section=Safety-and-Hazards |title=GHS Classification |website=pubchem.ncbi.nlm.nih.gov |date=2023-07-29 |access-date=2023-08-03}}</ref> |GHSPictograms = {{GHS07}} {{GHS08}} {{GHS09}} |GHSSignalWord = Warning |HPhrases = {{H-phrases|317|373|H410}} |PPhrases = {{P-phrases|260|261|272|273|280|302+352|319|321|333+313|362+364|391|501}} }} |Section4={{Chembox Related | OtherCompounds = Oxycarboxin }} }} '''Carboxin''' is a narrow-spectrum fungicide used as a seed treatment in agriculture to protect crops from fungal diseases. It was first marketed by Uniroyal in 1969 using their brand name '''Vitavax'''. The compound is a benzanilide analog that combines a heterocyclic acid with aniline to give an inhibitor of succinate dehydrogenase (SDHI).<ref name=PPDB/><ref name=Walter>{{cite book |doi=10.1002/9783527693931.ch31 |chapter=Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides |title=Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals |year=2016 |last1=Walter |first1=Harald |editor-last1=Lamberth |editor-first1=Clemens |editor-first2=Jürgen |editor-last2= Dinges |publisher=Wiley |pages=405–425 |isbn=9783527339471 }}</ref>
==Synthesis== The first synthesis of carboxin was disclosed in patents filed by Uniroyal.<ref>{{cite patent |country=US |number=3249499 |status=patent |gdate=1966-05-03 |fdate=1965-04-26 |pridate=1965-04-26 |invent1 =von Schmeling, B. |invent2 = Kulka, M. |invent3 = Thiara, D.S. |invent4 =Harrison, W.A. |title=Control of plant diseases |assign1=United States Rubber Co}}</ref> :500px Ethyl 2-chloroacetoacetate is treated with 2-mercaptoethanol and base, followed by cyclisation and water removal under acidic conditions. The resultant ethyl ester of the 1,4-oxathiine heterocycle is then formed into an amide with aniline using standard conditions via the carboxylic acid and acid chloride. This gives carboxin in high overall yield.<ref>{{cite journal |doi=10.1126/science.152.3722.659 |title=Systemic Fungicidal Activity of 1,4-Oxathiin Derivatives |date=1966 |last1=von Schmeling |first1=B. |last2=Kulka |first2=Marshall |journal=Science |volume=152 |issue=3722 |pages=659–660 |pmid=17779512 |bibcode=1966Sci...152..659V |s2cid=27561137 }}</ref> The compound has been crystallised in two polymorphic forms,<ref name=Frampton>{{cite journal |doi=10.1107/S2056989018015451 |doi-access=free|title=Two polymorphic forms of the oxathiin systemic fungicide active carboxine |date=2018 |last1=Frampton |first1=Christopher S. |last2=Frampton |first2=Eleanor S. |last3=Thomson |first3=Paul A. |journal=Acta Crystallographica Section E: Crystallographic Communications |volume=74 |issue=12 |pages=1741–1745 |pmid=30574366 |pmc=6281101 }}</ref> which have equal biological activity.<ref name=BCPC8>{{Cite book |isbn=0948404019 | title = The Pesticide Manual - A World Compendium | edition = Eighth | editor = Worthing C.R. | publisher = British Crop Protection Council | date = 1987|pages=136–7}}</ref>
== 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 succinate dehydrogenase (SDHI),<ref>{{cite journal |doi=10.1017/S0016672300016098 |title=Three genes determine the carboxin sensitivity of mitochondrial succinate oxidation in ''Aspergillus nidulans'' |date=1975 |last1=Gunatilleke |first1=I. A. U. N. |last2=Arst |first2=H. N. |last3=Scazzocchio |first3=C. |journal=Genetical Research |volume=26 |issue=3 |pages=297–305 |pmid=178574 |doi-access=free }}</ref> and later work showed that it binds to the quinone reduction site of the enzyme complex, preventing ubiquinone from doing so. As a consequence, the tricarboxylic acid cycle and electron transport chain cannot function.<ref>{{cite journal |doi=10.1074/jbc.M311876200 |doi-access=free |title=The Quaternary Structure of the Saccharomyces cerevisiae Succinate Dehydrogenase |year=2004 |last1=Oyedotun |first1=Kayode S. |last2=Lemire |first2=Bernard D. |journal=Journal of Biological Chemistry |volume=279 |issue=10 |pages=9424–9431 |pmid=14672929 }}</ref><ref>{{cite journal |doi=10.1016/j.cropro.2010.02.019 |title=Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi |year=2010 |last1=Avenot |first1=Hervé F. |last2=Michailides |first2=Themis J. |journal=Crop Protection |volume=29 |issue=7 |pages=643–651 }}</ref>
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.<ref name=Frampton/>
==Usage== Owing to its systemic properties, carboxin is suitable for use as a seed treatment 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 in cotton and vegetables.<ref name=Walter/><ref name=BCPC8/>
The compound was used in Australia, the EU, the UK and the US but registration has lapsed in the EU.<ref name=PPDB/> It was reported to have had a total worldwide sales of $75 million in 2014.<ref name=Walter/>{{rp|405}}
== Human safety == Carboxin has low mammalian toxicity and is not persistent in the environment.<ref name=PPDB/><ref name=EPA>{{cite web |url=https://nepis.epa.gov/Exe/ZyPURL.cgi?Dockey=2000D2LS.txt |title=Reregistration Eligibility Decision (RED) Fact Sheet for Carboxin |date=2004 |publisher=EPA }}</ref> One of its metabolites, the sulfone, is also active as an SDHI and has been sold as the fungicide oxycarboxin.<ref>{{cite web |url=http://sitem.herts.ac.uk/aeru/ppdb/en/Reports/500.htm |title=Oxycarboxin |publisher=University of Hertfordshire |author=Pesticide Properties Database |date=2023-06-15 |access-date=2023-08-07 }}</ref>
==Analogues== Carboxin was the first SDHI-type fungicide and its invention triggered a search for compounds with improved properties, particularly for active ingredients which would control a broader range of economically-important diseases.<ref>{{cite journal |doi=10.1584/jpestics.G10-70 |title=Structure-activity relationship of carboxin-related carboxamides as fungicide |date=2011 |last1=Yoshikawa |first1=Yukihiro |last2=Katsuta |first2=Hiroyuki |last3=Kishi |first3=Junro |last4=Yanase |first4=Yuji |journal=Journal of Pesticide Science |volume=36 |issue=3 |pages=347–356 |s2cid=85347084 |doi-access=free }}</ref> Boscalid, introduced in 2003, retained the aniline amide part-structure but with a pyridine ring in place of the 1,4-oxathiine and with a second benzene ring attached to the aniline portion. By 2014, it had annual sales of $390 million.<ref name=Walter/>
{{As of|2023}}, over 18 related amides had been marketed, with seven of these being derivatives of 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid.<ref name=Umetsu>{{cite journal |doi=10.1584/jpestics.D20-201 |title=Development of novel pesticides in the 21st century |year=2020 |last1=Umetsu |first1=Noriharu |last2=Shirai |first2=Yuichi |journal=Journal of Pesticide Science |volume=45 |issue=2 |pages=54–74 |pmid=33132734 |pmc=7581488 }}</ref> The Fungicides Resistance Action Committee (FRAC)<ref>{{cite web |url=https://www.frac.info/ |title=Fungicides Resistance Action Committee website}}</ref> assigns fungicides into classes so as to facilitate resistance management and SDHI form one group.<ref>{{cite web |url=https://www.frac.info/fungicide-resistance-management/by-fungicide-common-name |title=Search Fungicides to find FRAC Recommendations |publisher=Fungicides Resistance Action Committee |access-date=2023-08-03 }}</ref>
==Brands== Carboxin is the ISO common name<ref>{{cite web |url=http://www.bcpcpesticidecompendium.org/carboxin.html |title=Compendium of Pesticide Common Names: Carboxin |publisher=BCPC |access-date=2023-08-07}}</ref> 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.<ref name=PPDB/><ref name=BCPC8/>
==References== {{reflist}}
Category:Fungicides Category:Anilides Category:Heterocyclic compounds with 1 ring