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Carboxin

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Carboxin
Names
Preferred IUPAC name
2-methyl-N-phenyl-5,6-dihydro-1,4-oxathiine-3-carboxamide
Identifiers
3D model (JSmol)
983249
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.023.665 Edit this at Wikidata
EC Number
  • 226-031-1
UNII
  • InChI=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) checkY
    Key: GYSSRZJIHXQEHQ-UHFFFAOYSA-N checkY
  • CC1=C(SCCO1)C(=O)NC2=CC=CC=C2
Properties[1]
C12H13NO2S
Molar mass 235.3
Appearance Off-white solid
Density 1.45 g/cm3
Melting point 91.5°C
134 mg/L
log P 2.3
Hazards
GHS labelling:[2]
GHS07: Exclamation mark GHS08: Health hazard GHS09: Environmental hazard
Warning
H317, H373, H410
P260, P261, P272, P273, P280, P302+P352, P319, P321, P333+P313, P362+P364, P391, P501
Related compounds
Related compounds
 Oxycarboxin
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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 an anilide which combines a heterocyclic acid with aniline to give an inhibitor of succinate dehydrogenase (SDHI).[1][3]

Synthesis

[edit]

The first synthesis of carboxin was disclosed in patents filed by Uniroyal.[4]

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.[5] The compound has been crystallised in two polymorphic forms,[6] which have equal biological activity.[7]

Mechanism of action

[edit]

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),[8] 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.[9][10]

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.[6]

Usage

[edit]

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.[3][7]

The compound was used in Australia, the EU, the UK and the US but registration has lapsed in the EU.[1] It was reported to have had a total worldwide sales of $75 million in 2014.[3]: 405 

Human safety

[edit]

Carboxin has low mammalian toxicity and is not persistent in the environment.[1][11] One of its metabolites, the sulfone, is also active as an SDHI and has been sold as the fungicide oxycarboxin.[12]

Analogues

[edit]

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.[13] 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.[3]

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.[14] The Fungicides Resistance Action Committee (FRAC)[15] assigns fungicides into classes so as to facilitate resistance management and SDHI form one group.[16]

Brands

[edit]

Carboxin is the ISO common name[17] 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.[1][7]

References

[edit]
  1. ^ a b c d e Pesticide Properties Database (2023-07-21). "Carboxin". University of Hertfordshire. Retrieved 2023-08-03.
  2. ^ "GHS Classification". pubchem.ncbi.nlm.nih.gov. 2023-07-29. Retrieved 2023-08-03.
  3. ^ a b c d Walter, Harald (2016). "Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides". In Lamberth, Clemens; Dinges, Jürgen (eds.). Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals. Wiley. pp. 405–425. doi:10.1002/9783527693931.ch31. ISBN 9783527339471.
  4. ^ US patent 3249499, von Schmeling, B.; Kulka, M. & Thiara, D.S. et al., "Control of plant diseases", issued 1966-05-03, assigned to United States Rubber Co 
  5. ^ von Schmeling, B.; Kulka, Marshall (1966). "Systemic Fungicidal Activity of 1,4-Oxathiin Derivatives". Science. 152 (3722): 659–660. Bibcode:1966Sci...152..659V. doi:10.1126/science.152.3722.659. PMID 17779512. S2CID 27561137.
  6. ^ a b Frampton, Christopher S.; Frampton, Eleanor S.; Thomson, Paul A. (2018). "Two polymorphic forms of the oxathiin systemic fungicide active carboxine". Acta Crystallographica Section E: Crystallographic Communications. 74 (12): 1741–1745. doi:10.1107/S2056989018015451. PMC 6281101. PMID 30574366.
  7. ^ a b c Worthing C.R., ed. (1987). The Pesticide Manual - A World Compendium (Eighth ed.). British Crop Protection Council. pp. 136–7. ISBN 0948404019.
  8. ^ Gunatilleke, I. A. U. N.; Arst, H. N.; Scazzocchio, C. (1975). "Three genes determine the carboxin sensitivity of mitochondrial succinate oxidation in Aspergillus nidulans". Genetical Research. 26 (3): 297–305. doi:10.1017/S0016672300016098. PMID 178574.
  9. ^ Oyedotun, Kayode S.; Lemire, Bernard D. (2004). "The Quaternary Structure of the Saccharomyces cerevisiae Succinate Dehydrogenase". Journal of Biological Chemistry. 279 (10): 9424–9431. doi:10.1074/jbc.M311876200. PMID 14672929.
  10. ^ Avenot, Hervé F.; Michailides, Themis J. (2010). "Progress in understanding molecular mechanisms and evolution of resistance to succinate dehydrogenase inhibiting (SDHI) fungicides in phytopathogenic fungi". Crop Protection. 29 (7): 643–651. doi:10.1016/j.cropro.2010.02.019.
  11. ^ "Reregistration Eligibility Decision (RED) Fact Sheet for Carboxin". EPA. 2004.
  12. ^ Pesticide Properties Database (2023-06-15). "Oxycarboxin". University of Hertfordshire. Retrieved 2023-08-07.
  13. ^ Yoshikawa, Yukihiro; Katsuta, Hiroyuki; Kishi, Junro; Yanase, Yuji (2011). "Structure-activity relationship of carboxin-related carboxamides as fungicide". Journal of Pesticide Science. 36 (3): 347–356. doi:10.1584/jpestics.G10-70. S2CID 85347084.
  14. ^ Umetsu, Noriharu; Shirai, Yuichi (2020). "Development of novel pesticides in the 21st century". Journal of Pesticide Science. 45 (2): 54–74. doi:10.1584/jpestics.D20-201. PMC 7581488. PMID 33132734.
  15. ^ "Fungicides Resistance Action Committee website".
  16. ^ "Search Fungicides to find FRAC Recommendations". Fungicides Resistance Action Committee. Retrieved 2023-08-03.
  17. ^ "Compendium of Pesticide Common Names: Carboxin". BCPC. Retrieved 2023-08-07.
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