Isofetamid I Fungicides | Succinate Dehydrogenase Inhibitors (SDHIs)

Isofetamid [N-[1,1-dimethyl-2-(4-isopropoxy-o-tolyl)-2-oxoethyl]-3-methylthiophene-2-carboxamide] is a thiophene-carboxamide based succinate dehydrogenase inhibitor (SDHI)  fungicide launched in 2012 by Ishihara Sangyo Kaisha [1].

Isofetamid: 2D and 3D Structure

Isofetamid has been shown to be highly effective against Botrytis cinerea (grey mold) on grape. It is registered for the control of different Botrytis and Sclerotinia spp. on grape, lettuce, rapeseed, low growing berry, and turfgrass on golf courses.

Mechanism for Activity

Succinate dehydrogenase (SDH, complex II) or succinate:ubiquinone oxidoreductase (SQR) is an enzyme complex, bound to the inner mitochondrial membrane of mammalian mitochondria and many bacterial cells. SDH is the only enzyme involved in both respiratory chain and tricarboxylic acid (TCA) or Krebs cycle. In the inner mitochondrial membrane, SDH catalyzes the oxidation of succinate to fumarate, coupled with the reduction of ubiquinone to ubiquinol [2].

In agrochemical research, SDH was identified as a significant target for structurally diverse fungicides and acaricides. The fungicidal effect of nearly all SDH inhibitors relies on the disruption of the TCA cycle.

Isofetamid is a new succinate dehydrogenase inhibitor (SDHI) fungicide with a single-site of action that inhibits cellular respiration and appears to be a new option in the chemical treatment against gray mold.

Gray mold is an important disease in grapevines, and its control depends primarily on the use of fungicides with a single-site mode of action. Botrytis cinerea has a high risk of developing resistance against such fungicides. Therefore, novel chemical options are needed to achieve satisfactory control of gray mold where Isofetamid fits the bill perfectly.

Developer

It is developed by Ishihara Sangyo Kaisha and was launched in 2012.

Reported Activities for Isofetamid

EC₅₀ (Inhibition of Botrytis allii growth ) = 0.22 ug/ml

EC₅₀ (Inhibition of Botrytis cinerea growth ) = 0.1 ug/ml

EC₅₀ (Inhibition of Botrytis squamosa growth ) = 0.74 ug/ml

EC₅₀ (Inhibition of Botrytis tulipae growth ) = 0.36 ug/ml

Summary

Common name: Isofetamid; IKF-5411; IKF5411; IKF 5411

Trademarks: KENJA (36% SC)

Molecular Formula: C20H25NO3S

CAS Registry Number: 875915-78-9

CAS Name: N-[1,1-dimethyl-2-(4-isopropoxy-o-tolyl)-2-oxoethyl]-3-methylthiophene-2-carboxamide

Molecular Weight: 359.48

SMILES: O=C(C1=C(C)C=CS1)NC(C)(C)C(C2=CC=C(OC(C)C)C=C2C)=O

InChI Key: WMKZDPFZIZQROT-UHFFFAOYSA-N

InChI: InChI=1S/C20H25NO3S/c1-12(2)24-15-7-8-16(14(4)11-15)18(22)20(5,6)21-19(23)17-13(3)9-10-25-17/h7-12H,1-6H3,(H,21,23)

Mechanism of Action: Succinate Dehydrogenase Inhibitors (SDHIs)

Activity: Fungicide

Status: Launched 2012 (Japan)

Chemical Class: Amides containing; Sulphur containing; Thio containing; Thiophene containing; Small-molecules

Originator: Ishihara Sangyo Kaisha (ISK)

Isofetamid Synthesis

WO2006016708A1: The patent reports synthesis for Isofetamid and its various derivatives.

The first strategy to Isofetamid synthesis starts with Fridel Crafts acylation of m-cresol. The phenol end of cresol is esterified in the next step with iso-propyl bromide. Subsequent bromination of intermediate with phenyltrimethyl-ammonium tribromide gave the bromo intermediate compound, which reacted with sodium azide to yield intermediate azide. Finally, reduction of azide with H₂ yielded intermediate isofetamid amine, followed by a coupling reaction with 3-methylthiophene-2-carbonylchloride to give the title product, Isofetamid.

The second strategy starts with addition of 4-isopropoxy-2-methylbenzonitrile with isopropyl magnesium bromide forming the ester intermediate. Subsequent steps are same as reported above.

Identifications:

1H NMR (Estimated) for Isofetamid 

Adverse Reports:

Nothing available.

Others:

Acute oral (rat) LD₅₀ = greater than 2000 mg/kg

Acute dermal (rat) LD₅₀ = greater than 2000 mg/kg

Carp LC₅₀ (96 hr) = greater than 7.1 mg/L

Mutagenicity = Negative

The readers are welcome to share their views.

References:

1. Tsukuda, S. Developing trend of SDHI fungicide and studies on a novel fungicide, isofetamid. Japanese Journal of Pesticide Science 2014, 39(1), 89-95. (free article) {text in Japanese}

2. Yang, G. -F.; et. al. Succinate Dehydrogenase: An Ideal Target for Fungicide Discovery. Chap 13 In Discovery and Synthesis of Crop Protection Products; ACS Symposium Series; American Chemical Society: Washington, DC, 2015. (FMO only)

3. Nakamura, Y.; et. al. Fungicidal composition containing acid amide derivative. WO2006016708A1

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Tolprocarb | Fungicides I Polyketide Synthase Enzyme (PKS) Inhibitors

Tolprocarb [2,2,2-Trifluoroethyl-N-[(1S)-2-methyl-1-[[(4-methylbenzoyl)amino]methyl]propyl carbamate] is a novel new member of group of compounds that specifically block melanin biosynthesis in the pathogen, commonly referred to as conventional melanin biosynthesis inhibitors (cMBIs). It is developed as a fungicide to act against Magnaporthe grisea, the causal agent of rice blast. The novelty of Tolprocarb lies in its new and unique mechanism of action against the pathogen, which overcomes any form of resistance that pathogen, might have against the existing cMBIs.

Tolprocarb: 2D and 3D Structure

Tolprocarb is developed and launched by Mitsui Chemicals in 2012 with focus on the rice market, where Tolprocarb shows good control of Magnaporthe grisea.

Mechanism for Activity

Rice blast caused by Magnaporthe grisea is a major fungal disease affecting rice production worldwide. In its infection process, M. grisea produces unicellular infection structures, called appressoria, which adhere tightly to the host surface and produce slender infection pegs that pierce the underlying cell wall of the host. The cell wall of appressoria contains a dense layer of 1,8-dihydroxynaphthalene (1,8-DHN)-melanin synthesized from 1,8-DHN. The accumulation of the dark-colored 1,8-DHN-melanin between the plasma membrane and the cell wall is an essential step before the appressoria of Magnaporthe and other fungal species can penetrate host plants.

It is also known that 1,8-DHN-melanin-deficient mutants of M. grisea, which cannot produce the dark gray pigment typical of wildtype mycelia failed to infect intact host plants.

In various fungal species (e.g., M. grisea, etc), biochemical analysis of enzymes involved in the melanin biosynthetic pathway has been reported.

The biosynthetic pathway for melanin in fungi starts from pentaketide synthesis and cyclization to form 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) by polyketide synthase (PKS). The subsequent steps entail reduction of 1,3,6,8-THN to scytalone, dehydration of scytalone to 1,3,8-trihydroxynaphthalene (1,3,8-THN), reduction of 1,3,8-THN to vermelone, and dehydration of vermelone to 1,8-dihydroxynaphthalene (1,8-DHN). 1,8-DHN is then polymerized and oxidized to yield melanin [1].

While other cMBIs such as tricyclazole, pyroquilon, carpropamid, diclocymet are known to inhibit either reductase or dehydratase enzymes in the melanin biosynthesis pathway, Tolprocarb is unique in that it inhibits the polyketide synthase enzyme (PKS).

Developer

Tolprocarb is developed and launched as a fungicide by Mitsui Chemicals in 2012. Tolprocarb showed a high controlling effect on rice blast by both nursery box application and broadcasting on paddy rice, and its practical value has been verified.

Reported Activities for Tolprocarb

IC₅₀ (Inhibition of polyketide synthase activity) = 0.03 uM

IC₉₀ (Inhibition of polyketide synthase activity) = 0.23 uM

Summary

Common name: Tolprocarb; MTF-0301; MTF0301; MTF 0301

Trademarks: -

Molecular Formula: C16H21F3N2O3

CAS Registry Number: 911499-62-2

CAS Name: (S)-2,2,2-trifluoroethyl (3-methyl-1-(4-methylbenzamido)butan-2-yl)carbamate

Molecular Weight: 346.34

SMILES: FC(F)(COC(N[C@@H](C(C)C)CNC(C1=CC=C(C)C=C1)=O)=O)F

InChI Key: RSOBJVBYZCMJOS-CYBMUJFWSA-N

InChI: InChI=1S/C16H21F3N2O3/c1-10(2)13(21-15(23)24-9-16(17,18)19)8-20-14(22)12-6-4-11(3)5-7-12/h4-7,10,13H,8-9H2,1-3H3,(H,20,22)(H,21,23)/t13-/m1/s1

Mechanism of Action: Polyketide Synthase Enzyme (PKS) Inhibitors

Activity: Fungicide

Status: Launched 2012 (Japan)

Chemical Class: Flourine Containing; Tri-Flouro Molecules; Amides; Small-molecules; L-valine containing; Amino acid containing

Originator: Mitsui Chemicals

Tolprocarb Synthesis

WO2012039132A1: The patent reports synthesis for Tolprocarb and its various derivatives. The synthesis starts with condensation between trifluoroethyl chloroformate and L-valine. The carbamate thus obtained is then treated sequentially with phosgene and ammonia to yield carboxamide, which is again reacted with phosgene to afford the nitrile intermediate. Palladium catalyzed hydrogenation of cyano-intermediate, followed by amidation and reaction with activated 4-methylbenzoic acid, yields Tolprocarb in 75% overall yield.

Identifications:

1H NMR (Estimated) for Tolprocrab

Experimental: ¹H NMR (CDCl₃) δ 0.96-1.03 (6H, m), 1.85-1.91 (1H, m), 2.39 (3H, s), 3.46-3.51 (1H, m), 3.61-3.72 (2H, m) , 4.35-4.46 (2H, m), 5.26 (1H, d, J = 8.30Hz), 6.62 (1H, brs), 7.21-7.23 (2H, m), 7.63-7.65 (2H, m).

Adverse Reports:

Nothing available.

Others:

The readers are welcome to share their views.

References:

1. Hamada, T.; et. al. Action mechanism of the novel rice blast fungicide tolprocarb distinct from that of conventional melanin biosynthesis inhibitors. J Pestic Sci 2014, 39(3), 152-158. (free article)

2. Umetani, H.; et. al. Method for producing amino acid amide derivative having fluorine-containing carbamate group, production intermediate thereof, and method for producing ethylene diamine derivative. WO2012039132A1

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Fluensulfone I Nematicides

Fluensulfone [5-chloro-2-(3,4,4-trifluorobut-3-enylsulfonyl)-1,3-thiazole] is a new nematicide for chemical control of Plant Parasitic Nematodes (PPNs). Chemically, Fluensulfone is a member of the fluoroalkenyl thioether group and it is designed in manner that it posses excellent nematicidal activity but lacks many of the drawbacks of other chemical controls, as exemplified by its relatively low toxicity to non-target organisms.

Fluensulfone is effective against a number of PPNs including species of Meloidogyne which are responsible for a significant proportion of nematode crop yield loss. Also, Fluensulfone has been shown to significantly reduce root infection and penetration by Meloidogyne javanica, Meloidogyne incognita and Meloidogyne arenaria.

Fluensulfone: 2D and 3D Structure

Fluensulfone was launched in 2014 by ADAMA which claims it to be “true nematicide“ as it causes irreversible nematicidal activity resulting in pest mortality within 24 to 48 hours rather than temporary nematostatic (repelling or immobilizing) activity as seen with organophosphates and carbamates.

Mechanism for Activity

There is no mechanism available right now.

In a study using model genetic organism Caenorhabditis elegans proved that C. elegans is susceptible to the irreversible nematicidal effects of Fluensulfone. Researchers found that:

a. Fluensulfone has pleiotropic actions.

b. It inhibits development, egg-laying, egg-hatching, feeding and locomotion. In the case of feeding and locomotion, an early excitation precedes the gross inhibition.

The profile of these effects is notably distinct from other classes of anthelmintic and nematicide: the inhibition of motility caused by Fluensulfone is not accompanied by the hypercontraction which is characteristic of organophosphates and carbamates. Also, C. elegans mutants that are resistant to the carbamate Aldicarb and the macrocyclic lactone Ivermectin retain susceptibility to Fluensulfone.

Whilst the dose required is higher than that which has nematicidal activity against Meloidogyne spp. the profile of effects on motility, egg-hatching and survival is similar to that reported for plant parasitic nematodes. These data indicate Fluensulfone’s mode of action is distinct from currently available nematicides and it therefore presents a promising new chemical entity for crop protection [1].

Developer

It is developed and launched by ADAMA in 2014.

Reported Activities for Fluensulfone

% Mortality (C. elegans life cycle [L1] @ 1 mM) = 100 ± 0

% Mortality (C. elegans life cycle [Adult] @ 1 mM) = 97.0 ± 12

Summary

Common name: Dipymetitrone; MCW-2

Trademarks: NIMITZ

Molecular Formula: C7H5ClF3NO2S2

CAS Registry Number: 318290-98-1

CAS Name: 5-chloro-2-((3,4,4-trifluorobut-3-en-1-yl)sulfonyl)thiazole

Molecular Weight: 291.70

SMILES: F/C(CCS(C1=NC=C(Cl)S1)(=O)=O)=C(F)/F

InChI Key: XSNMWAPKHUGZGQ-UHFFFAOYSA-N

InChI: InChI=1S/C7H5ClF3NO2S2/c8-5-3-12-7(15-5)16(13,14)2-1-4(9)6(10)11/h3H,1-2H2

Mechanism of Action: Unknown

Activity: Nematicide

Status: Launched 2014 (US)

Chemical Class: Thiazoles; Sulfonyls; Flourine Containing; Tri-Flouro Molecules; Sulphur containing; Thio containing; Small-molecules

Originator: ADAMA

Fluensulfone Synthesis

WO2001002378A1: The patent reports synthesis for Fluensulfone and its various derivatives. The synthesis starts with the alklylation of the 2-mercaptothiazole by 4-bromo-1,1,2-trifluorobutene. The thiazole obtained is subsequently chlorinated by N-chlorosuccinimide, and the sulfide function oxidized to the sulphone by hydrogen peroxide in the presence of acetic acid.

 Identifications:

1H NMR (Estimate) for Fluensulfone

Adverse Reports:

Nothing available.

Others:

The readers are welcome to share their views.

References:

1. Kearn, J.; et. al. Fluensulfone is a nematicide with a mode of action distinct from anticholinesterases and macrocyclic lactones. Pestic Biochem Physiol 2014, 109, 44-57. (free article)

2. Watanabe, Y.; et. al. Nematicidal trifluorobutenes. WO2001002378A1

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Dipymetitrone | Fungicides

Dipymetitrone [2,6-dimethyl-[1,4]dithiino[2,3-c:5,6-c']dipyrrole-1,3,5,7(2H,6H)-tetraone] is a fungicide launched by Bayer CropScience in 2014.

Dipymetitrone: 2D and 3D Structure

The biochemical activities of Dithiine-tetracarboximides as already known; such as:

a: Anthelmintics against internal parasites of animals, in particular against nematodes.

b: Insecticidal activity.

c: Antibacterial effect against pathogens causing mycoses in humans.

Furthermore, it is known that Dithiine-tetracarboximides can be used as pigments in electrophotographic photoreceptors or as colorants in paints and polymers [1, 2].

Mechanism for Activity

There is no mechanism available right now.

Developer

It is developed and launched by Bayer Cropscience in 2014.

Reported Activities for Dipymetitrone

No data is reported.

Summary

Common name: Dipymetitrone

Trademarks: -

Molecular Formula: C10H6N2O4S2

CAS Registry Number: 16114-35-5

CAS Name: 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c']dipyrrole-1,3,5,7(2H,6H)-tetrone

Molecular Weight: 282.30

SMILES: O=C(C1=C2SC3=C(C(N(C)C3=O)=O)S1)N(C)C2=O

InChI Key: FPKXBFWMIYHCID-UHFFFAOYSA-N

InChI: InChI=1S/C10H6N2O4S2/c1-11-7(13)3-4(8(11)14)18-6-5(17-3)9(15)12(2)10(6)16/h1-2H3

Mechanism of Action: Unknown

Activity: Fungicides; Anthelmintics; Insecticidal; Antibacterial

Status: Launched 2014 (US)

Chemical Class: Sulphur containing; Thio containing; Small-molecules; Dithiine-tetracarboximides

Originator: Bayer CropScience

Dipymetitrone Synthesis

WO2012028588A1: The process appears to industrial preparation of Dipymetitrone. It involves atypical oxidation reaction by thionyl chloride. The synthesis starts from the reaction of methylamine and succinic anhydride to afford 4-amino-4-oxobutanoic acid. Treatment of 4-amino-4-oxobutanoic acid with thionyl chloride and isomerization of the intermediate diisomaleimide-dithiine with water yields Dipymetitrone. See also Ref 2, 3.

US3364229A: It is the oldest reported synthesis for Dipymetitrone. The process suffers from failures as the handling of the highly toxic hydrogen sulfide gas is technically very difficult and costly. When using thiourea unwanted byproducts other than the target product obtained, which are very difficult to remove and the achievable yields deteriorate. See aslo Ref 4.

 Identifications:

1H NMR (Estimated) for Dipymetitrone

Adverse Reports:

Nothing available.

Others:

The readers are welcome to share their views.

References:

1. Geller, T.; A process for preparing dithiin-tetracarboximiden. WO2012028588A1

2. Seitz, T.; et. al. Verwendung von dithiin-tetracarboximiden zum bekämpfen phytopathogener pilze. WO2010043319A1

3. Draber, W.; et. al. 1, 4 dithiin-2,3,5,6-tetracarboximides and process for their preparation. US3364229A

4. Valla, A.; et. al. Atypical Oxidation Reaction by Thionyl Chloride: Easy Two-Step Synthesis of N-Alkyl-1,4-dithiines. Syn Comm 2006, 36(23), 3591-3597. (FMO only) [It reports mechanism for reaction involving thionly chloride].

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