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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