pydiflumetofen

{{chembox

|ImageFile = Pydiflumetofen.svg

|PIN = 3-(Difluoromethyl)-N-methoxy-1-methyl-N-[1-(2,4,6-trichlorophenyl)-2-propanyl]-1H-pyrazole-4-carboxamide

|OtherNames = SYN545974

|Section1 ={{Chembox Identifiers

|CASNo_Ref = {{cascite|correct|CAS}}

|CASNo= 1228284-64-7

|Beilstein = 20345474

|ChEBI_Ref = {{ebicite|correct|EBI}}

|ChEBI = 87576

|ChEMBL_Ref = {{ebicite|correct|EMBL}}

|ChEMBL =

|ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

|ChemSpiderID = 34501423

|EC_number = 817-852-1

|PubChem= 56933411

|KEGG_Ref = {{keggcite|correct|kegg}}

|KEGG =

|UNII = WHG7I49FAK

|StdInChI_Ref = {{stdinchicite|correct|chemspider}}

|StdInChI = 1S/C16H16Cl3F2N3O2/c1-8(4-10-12(18)5-9(17)6-13(10)19)24(26-3)16(25)11-7-23(2)22-14(11)15(20)21/h5-8,15H,4H2,1-3H3

|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

|StdInChIKey = DGOAXBPOVUPPEB-UHFFFAOYSA-N

|SMILES = CC(CC1=C(C=C(C=C1Cl)Cl)Cl)N(C(=O)C2=CN(N=C2C(F)F)C)OC

}}

|Section2={{Chembox Properties

|Properties_ref ={{cite web |url=http://sitem.herts.ac.uk/aeru/ppdb/en/Reports/3086.htm |title=Pydiflumetofen |publisher=University of Hertfordshire |author=Pesticide Properties Database }}

|C=16 |H=16 |Cl=3 |F=2 |N=3 |O=2

|MolarMass= 426.67

|Appearance= Off-white solid

|Density= g/cm³

|MeltingPt= 113°C

|Solubility= 1.5 mg/L (20 °C)

|LogP= 3.8

}}

|Section3={{Chembox Hazards

|GHS_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=2023-07-22 |access-date=2023-07-27}}

|GHSPictograms = {{GHS08}} {{GHS09}}

|GHSSignalWord = Warning

|HPhrases = {{H-phrases|351|361f|H410}}

|PPhrases = {{P-phrases|203|273|280|318|391|405|501}}

}}

Pydiflumetofen belongs to the large family of SDHI pesticides, it is used as broad spectrum fungicide in agriculture to protect crops from fungal diseases. It was first marketed by Syngenta in 2016 using their brand name Miravis. The compound is an methoxy amide which combines a pyrazole acid with a substituted amphetamine to give an inhibitor of succinate dehydrogenase,{{cite web |url=https://www.fao.org/fileadmin/user_upload/IPM_Pesticide/JMPR/Evaluations/2018/Pydiflumetofen__309_.pdf |title=Pydiflumetofen |author-first=Makoto |author-last=Irie |date=2017 |access-date=2023-07-27 |publisher=FAO }} an enzyme that is important to cellular respiration in almost all living organisms.{{cite journal |doi=10.1371/journal.pone.0224132 |doi-access=free |title=Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells |date=2019 |last1=Bénit |first1=Paule |last2=Kahn |first2=Agathe |last3=Chretien |first3=Dominique |last4=Bortoli |first4=Sylvie |last5=Huc |first5=Laurence |last6=Schiff |first6=Manuel |last7=Gimenez-Roqueplo |first7=Anne-Paule |last8=Favier |first8=Judith |last9=Gressens |first9=Pierre |last10=Rak |first10=Malgorzata |last11=Rustin |first11=Pierre |display-authors=3 |journal=PLOS ONE |volume=14 |issue=11 |pages=e0224132 |pmid=31697708 |pmc=6837341 |bibcode=2019PLoSO..1424132B }}

History

Inhibition of succinate dehydrogenase, the complex II in the mitochondrial respiration chain, has been known as a fungicidal mechanism of action since the first examples were marketed in the 1960s. The first compound in this class was carboxin, which had a narrow spectrum of useful biological activity, mainly on basidiomycetes and was used as a seed treatment.{{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=978-3-527-33947-1 }}{{cite web |url=https://www.frac.info/frac-teams/working-groups/sdhi-fungicides/information |title=History of SDHI-fungicides |website=frac.info |access-date=2023-07-26 }} By 2016, at least 17 further examples of this mechanism of action were developed by crop protection companies, with the market leader being boscalid, owing to its broader spectrum of fungal species controlled. However, it lacked full control of important cereal diseases, especially septoria leaf blotch Zymoseptoria tritici.

File:Pyrazole SDHI intermediate.svg

A group of compounds which did control septoria were amides of pyrazole-4-carboxylic acid, with the most successful being derivatives with an N-methyl group and a difluromethyl group in position 3 of the ring. These include penthiopyrad and fluxapyroxad.{{cite web |url=http://www.bcpcpesticidecompendium.org/class_fungicides.html#pyrazolecarboxamide_fungicides |title=Pyrazolecarboxamide fungicides |access-date=2023-07-27 |publisher=BCPC}} Research chemists at Syngenta made many analogues of this type{{cite journal |doi=10.1007/s00706-017-2101-y |title=Synthesis of fungicidally active succinate dehydrogenase inhibitors with novel difluoromethylated heterocyclic acid moieties |year=2018 |last1=Walter |first1=Harald |last2=Lamberth |first2=Clemens |last3=Corsi |first3=Camilla |journal=Monatshefte für Chemie - Chemical Monthly |volume=149 |issue=4 |pages=791–799 |s2cid=103548298 }} in the search for new products and by 2008 had discovered benzovindiflupyr, isopyrazam, sedaxane and pydiflumetofen.

Synthesis

Pydiflumetofen combines 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid with a novel amine derivative which was made from 2,4,6-trichlorobenzaldehyde.{{cite patent |country=US |number=8258169 |status=patent |title=Pyrazole-4-N-alkoxycarboxamides as microbiocides |pubdate=2012-09-04 |fdate=2009-12-01 |pridate=2008-12-05 |invent1=Rajan, R |invent2=Walter, H |invent3=Stierli, D |assign1=Syngenta Crop Protection }}

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A nitrostyrene is formed in a Henry reaction between the aldehyde and nitroethane. A reduction reaction converts it to a ketone which forms an ketoxime with methoxyamine. This, in turn, is reduced with sodium cyanoborohydride to give the amine required for amide formation with the acid chloride of the pyrazole.

Mechanism of action

Succinate dehydrogenase inhibitors (SDHI) of this type act by binding at 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.{{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 }}{{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 |bibcode=2010CrPro..29..643A }}{{cite journal |doi=10.2903/j.efsa.2019.5821 |doi-access=free |title=Peer review of the pesticide risk assessment of the active substance pydiflumetofen |year=2019 |last1=Arena |first1=Maria |last2=Auteri |first2=Domenica |last3=Brancato |first3=Alba |last4=Bura |first4=Laszlo |last5=Carrasco Cabrera |first5=Luis |last6=Chaideftou |first6=Eugenia |last7=Chiusolo |first7=Arianna |last8=Court Marques |first8=Daniele |last9=Crivellente |first9=Federica |last10=De Lentdecker |first10=Chloe |last11=Egsmose |first11=Mark |last12=Fait |first12=Gabriella |last13=Ferreira |first13=Lucien |last14=Greco |first14=Luna |last15=Ippolito |first15=Alessio |last16=Istace |first16=Frederique |last17=Jarrah |first17=Samira |last18=Kardassi |first18=Dimitra |last19=Leuschner |first19=Renata |last20=Lostia |first20=Alfonso |last21=Lythgo |first21=Christopher |last22=Mangas |first22=Iris |last23=Miron |first23=Ileana |last24=Molnar |first24=Tunde |last25=Padovani |first25=Laura |last26=Parra Morte |first26=Juan Manuel |last27=Pedersen |first27=Ragnor |last28=Reich |first28=Hermine |last29=Santos |first29=Miguel |last30=Serafimova |first30=Rositsa |journal=EFSA Journal |volume=17 |issue=10 |pages=e05821 |pmid=32626121 |pmc=7008818 |display-authors=3 }}

Usage

Pydiflumetofen has fungicidal effects against a wide range of crop pests. These include Alternaria, grey mould (Botrytis cinerea), Cercospora (leaf spot), septoria, powdery mildews (e.g. Uncinula necator), and scab (e.g. Venturia pyrina). As a result, it has potential use in crops including cereals, corn, soybeans, vegetables, peanut, curcubits, potato and fruit.{{cite journal |doi=10.1016/j.pestbp.2019.06.017 |title=Bioactivity, physiological characteristics and efficacy of the SDHI fungicide pydiflumetofen against Sclerotinia sclerotiorum |year=2019 |last1=Huang |first1=Xue-Ping |last2=Luo |first2=Jian |last3=Li |first3=Bei-Xing |last4=Song |first4=Yu-fei |last5=Mu |first5=Wei |last6=Liu |first6=Feng |journal=Pesticide Biochemistry and Physiology |volume=160 |pages=70–78 |pmid=31519259 |s2cid=198268036 }}{{cite journal |doi=10.1094/pdis-05-18-0763-re |title=Pharmacological Characteristics and Control Efficacy of a Novel SDHI Fungicide Pydiflumetofen Against Sclerotinia sclerotiorum |year=2019 |last1=Duan |first1=Yabing |last2=Xiu |first2=Qian |last3=Li |first3=Haoran |last4=Li |first4=Tao |last5=Wang |first5=Jianxin |last6=Zhou |first6=Mingguo |journal=Plant Disease |volume=103 |issue=1 |pages=77–82 |pmid=30358507 |s2cid=53022480 |doi-access=free }}{{cite web |url=https://www.syngenta-us.com/current-label/miravis |title=Miravis fungicide |access-date=2023-07-27 |author=Syngenta US |date=2021}}

The compound was introduced in the US in 2018 but estimated usage that year was low at only {{convert|4000|lb|kg}}.{{cite web |url=https://water.usgs.gov/nawqa/pnsp/usage/maps/show_map.php?year=2018&map=PYDIFLUMETOFEN&hilo=L&disp=Pydiflumetofen |title=Estimated Agricultural Use for pydiflumetofen, 2018 |author=US Geological Survey |date=2021-10-12 |access-date=2023-07-26 }} The compound is registered for use on peanut and fruits. {{As of|2023}} the compound is also registered in Argentina, Australia, Canada and New Zealand.{{cite web |url=https://www.syngenta.com/en/protecting-crops/products-list/adepidynr-technology |title=ADEPIDYN® technology |access-date=2023-07-27 |website=syngenta.com}}

Human safety

Pydiflumetofen has low acute toxicity:{{rp|8}} the Codex Alimentarius database maintained by the FAO lists the maximum residue limits for it in various food products.{{cite web |url=http://www.fao.org/fao-who-codexalimentarius/codex-texts/dbs/pestres/pesticide-detail/en/?p_id=309 |title=Pydiflumetofen |author=FAO / WHO }}

Environmental effects

The compound is very persistent in field conditions and its environmental fate and consequent ecotoxicology have been reviewed.{{rp|11–15}} In one laboratory study, the R enantiomer of the compound was shown to be more toxic to zebrafish, which was interpreted to be owing to its higher potency as an SDHI inhibitor than the S isomer.{{cite journal |doi=10.1016/j.envint.2022.107406 |doi-access=free |title=Comprehensive study of pydiflumetofen in Danio rerio: Enantioselective insight into the toxic mechanism and fate |year=2022 |last1=Wang |first1=Zhen |last2=Tan |first2=Yuting |last3=Li |first3=Yanhong |last4=Duan |first4=Jinsheng |last5=Wu |first5=Qiqi |last6=Li |first6=Rui |last7=Shi |first7=Haiyan |last8=Wang |first8=Minghua |journal=Environment International |volume=167 |page=107406 |pmid=35850082 |bibcode= 2022EnInt.16707406W|s2cid=250463420 }}{{cite journal |doi=10.1002/ps.6389 |title=Evaluation of exploitive potential for higher bioactivity and lower residue risk enantiomer of chiral fungicide pydiflumetofen |year=2021 |last1=Wang |first1=Zhen |last2=Li |first2=Rui |last3=Zhang |first3=Jing |last4=Liu |first4=Shiling |last5=He |first5=Zongzhe |last6=Wang |first6=Minghua |journal=Pest Management Science |volume=77 |issue=7 |pages=3419–3426 |pmid=33797181 |s2cid=232763150 }}

Resistance management

Fungal populations have the ability to develop resistance to SDHI inhibitors.{{cite journal |doi=10.1094/pdis-03-20-0487-re |title=Identification and Characterization of Fungicide Resistance in Botrytis Populations from Small Fruit Fields in the Mid-Atlantic United States |year=2021 |last1=Cosseboom |first1=Scott |last2=Hu |first2=Mengjun |journal=Plant Disease |volume=105 |issue=9 |pages=2366–2373 |pmid=33719541 |s2cid=232231834 |doi-access=free }} This potential can be mitigated by careful management. Reports of individual pest species becoming resistant are monitored by manufacturers, regulatory bodies such as the EPA and the Fungicides Resistance Action Committee (FRAC).{{cite web |url=https://www.frac.info/ |title=Fungicides Resistance Action Committee website}} The risks of resistance developing can be reduced by using a mixture of two or more fungicides which each have activity on relevant pests but with unrelated mechanisms of action. FRAC assigns fungicides into classes so as to facilitate this.{{cite web |url=https://www.frac.info/fungicide-resistance-management/by-fungicide-common-name |title=Search Fungicides to find FRAC Recommendations |access-date=2020-09-04 }}

Brands

Pydiflumetofen is the ISO common name{{cite web |url=http://www.bcpcpesticidecompendium.org/pydiflumetofen.html |title=Compendium of Pesticide Common Names: Pydiflumetofen |publisher=BCPC |access-date=2023-07-27}} for the active ingredient which is formulated into the branded product sold to end-users. Miravis is the brand name for Syngenta's suspension concentrate, which it also calls Adepidyn technology. The Miravis brand line includes other products containing pydiflumetofen mixed with other fungicidal active ingredients. These include Miravis Duo and Miravis Top (containing difenoconazole), Miravis Neo (containing propiconazole and azoxystrobin), and Miravis SBX (containing difenoconazole and azoxystrobin).{{Cite web |title=Chemical Name: Pydiflumetofen {{!}} US EPA |url=https://ordspub.epa.gov/ords/pesticides/f?p=113:6:::::P6_XCHEMICAL_ID:29191 |access-date=June 5, 2024 |website=Pesticide Product and Label System}}

Trebuset is the brand name for Syngenta's flowable concentrate formulation for use as a seed treatment.{{Cite web |title=Trebuset - Seed Treatment Product & Label Information {{!}} Syngenta US |url=https://www.syngenta-us.com/seed-treatment/trebuset |access-date=2024-06-05 |website=www.syngenta-us.com}}