Synthesis and Biological Activity of a Novel Acaricide, Pyflubumide

Chapter 27

Downloaded by CENTRAL MICHIGAN UNIV on December 8, 2015 | http://pubs.acs.org Publication Date (Web): November 4, 2015 | doi: 10.1021/bk-2015-1204.ch027

Synthesis and Biological Activity of a Novel Acaricide, Pyflubumide Takashi Furuya,1,* Motofumi Nakano,1 Akiyuki Suwa,1 Noriaki Yasokawa,2 Shinsuke Fujioka,2 and Kozo Machiya3 1Research

Center, Research & Development division, Nihon Nohyaku Co., Ltd., 345 Oyamada-cho, Kawachi-nagano, Osaka 586-0094, Japan 2Development department, Research & Development Division, Nihon Nohyaku Co., Ltd., 19-8, Kyobashi 1-Chome, Chuo-ku, Tokyo 104-8386, Japan 3Research & Development strategy department, Research & Development division, Nihon Nohyaku Co., Ltd., 19-8, Kyobashi 1-Chome, Chuo-ku, Tokyo 104-8386, Japan *E-mail: [email protected]

Various carboxamides that inhibit succinate dehydrogenase have been created and developed. Although succinate dehydrogenase plays an important role in energy metabolism in aerobic organisms, the practical usage of the carboxamides had been primarily limited to disease control. The study to create a new carboxamide molecule revealed that introducing a fluoroalkyl group at the 4′-position on the anilino moiety remarkably enhanced the acaricidal activity. This finding prompted extensive research to ultimately identify pyflubumide, a novel complex II-inhibiting acaricide.

Introduction Phytophagous mites are known as serious pests and some of them are notorious for their rapid development of resistance to agrochemicals. Therefore, new acaricides that are effective against the resistant population to the existing agrochemicals are always desired. Low toxicities against beneficial arthropods and natural enemies are also important for a novel acaricide in order to fit well into Integrated Pest Management (IPM) programs. © 2015 American Chemical Society In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Pyflubumide (Figure 1) is a novel caboxanilide that shows remarkable activity against spider mites of the genus Tetranychus and Panonychus including resistant strains collected from the field.

Figure 1. Chemical structure, nomenclature and profile of pyflubumide In this paper the discovery of pyflubumide are described, and the structureactivity relationships for the acaricidal activity and other biological activity are discussed.

Discovery of Acaricidal Activity The discovery of pyflubumide originated from our interest in the various succinate dehydrogenase inhibitors (SDHI). These carboxamides such as flutolanil have been used as important tools for controlling some diseases caused by basidiomycetes. The spectrum of these carboxamides had been considered specific. However, in the late 1990’s, it was reported that penthiopyrad, the carboxamide with an ortho-branched alkyl chain, exhibited a broader spectrum of activity (1). Meanwhile, flubendiamide, a novel insecticide with unique heptafluoroisopropyl substituent was reported by our colleagues (2, 3). We have synthesized various heptafluoroalkyl derivatives (4) but fungicide derivatives have never been synthesized. We were very interested in introducing heptafluoroisopropyl substituent to the carboxamide and synthesized the hybrid analogue 1 (Figure 2). It only showed low fungicidal activity. This low fungicidal activity seemed to be attributed to the 380 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


high lipophilicity of the compound, and the less lipophilic derivative 2 was then synthesized. The derivative 2 did not improve the fungicidal activity, however, it showed low larvicidal activity against spider mites (5).

Figure 2. Discovery of acaricides

This acaricidal activity attracted our attention as so far mitochondrial complex II-inhibiting carboxamides were primarily known to deliver fungicidal activity, and acaricidal activity had never been reported for these fungcidal compounds. Considering the structural similarity between this compound and SDHI carboxamides, we assumed that this acaricidal activity could be derived from an inhibition of mitochondrial complex II. Base on this idea, the compound 2 was modified by referring to the structures of SDHI carboxamides.

Optimization of Structures First, the acid moiety was modified by referring to the structures of SDHI carboxamides. As a result, we found that the furametpyr derivative 3 showed higher activity. Then the substituents on the pyrazole ring were examined and the 1, 3, 5-trimethylpyrazole derivative 4 found to be best (Figure 3) (6). 381 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Figure 3. Modification of acid moiety

Next, the effect of the substituents on the 2′- and 3′-positon was examined. The effect of the 2′-substituents R on the anilino moiety was shown in Table 1. The activity was strongly influenced by the number of carbon atoms and type of chain branching. Alkyl chain was required for the acaricidal activity and 1, 3-dimethylbutyl derivative 4 with the same substituent as penthiopyrad found to be best (6). The effect of the 3′-substituents on the anilino moiety was shown in Table 2. By referring to the meta-substituted carboxamide flutolanil, isopropyloxy derivative 10 was synthesized and it showed moderate activity. From the result of 2′-substituted derivatives, substitution for alkyl chain seemed to be effective. 3′-alkyl derivatives (compound 11-14) were synthesized and the derivative 13 having the same type of chain branching as flutolanil found to be best. The activity of 3′-isobutyl derivative 13 was comparable to that of 2′-(1, 3-dimethylbutyl) derivative 4. From the results shown in Table 1 and 2, it was concluded that an alkyl chain at the 2′- or 3′-position was required for the acaricidal activity and the favorable substituents were different between positions (2′- and 3′-) (6). Finally, compounds 4 and 13 were optimized (Table 3). We examined the effect of N-substituent Y and C(CF3)2Z on the 2′-(1, 3-dimethylbutyl) derivatives (type A) and the 3′-isobutyl derivatives (type B), respectively. In type A, N-acyl-substituted compounds retained high activity. In type B, N-acyl-substituted compounds retained or increased the activity. The compound 20, 23 and pyflubumide showed excellent activity. In view of their residual efficacy in the pot tests (data not shown), pyflubumide was selected as the developed compound (6).

382 In Discovery and Synthesis of Crop Protection Products; Maienfisch, et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2015.


Table 1. Effects of 2′-substitutents R on T. urticae activity a



Table 2. Effects of 3′-substituents R on T. urticae activity a



Table 3. Effect of the substituents Y and Z on the activity against T. urticae a


Synthesis of Pyflubumide


Synthetic pathway of pyflubumide is shown in Scheme 1 (6–8).

Scheme 1. Synthesis of pyflubumide

3-Isobutyl aniline 24 was heptafluoroisopropylated to give 25. The fluorine on the benzyl position of 25 was converted to methoxy group to give 26. The aniline 26 was reacted with 1, 3, 5-trimethylpyrazole carboxylic acid chloride to give the pyrazole carboxanilide 22, followed by acylation to give pyflubumide.

Biological Properties of Pyflubumide Acaricidal Activity, Resistance and Cross-Resistance Pyflubumide showed remarkable activities against not only Tetranychus species but also Panonychus species of mites (Table 4). In addition, the acaricidal activities of pyflubumide and the conventional acaricides against the field populations of mites were examined. Pyflubumide showed excellent activity against the field populations of mites which had developed resistance to conventional acaricides (Table 4). These results indicate that this acaricide is an effective new tool for controlling spider mites which had developed resistance to existing acaricides (6).


Mode of Action Our study revealed that the metabolite of pyflubumide (compound 22) is an inhibitor of the electron transport in mitochondrial complex II (9). Compound 22 shows the same inhibitory effect as described previously for beta-ketonitrile acaricides (10, 11). However, it was reported that their binding sites on mitochondrial complex II and/or the manners of binding are not identical (9).


Table 4. Acaricidal activity of pyflubumide and the conventional acaricides a Species

T. urticae

P. citri

a

LC50 (mg a. i. /L)

Collected site

Pyflubumide

Fenpyroximate

Acequinocyl

Etoxazol

Kumamoto

0.5

> 50

> 150

> 50

Itayanagi

0.9

> 50

> 150

> 50

Suzaka

2.3

> 50

> 150

> 50

Susceptible strain

1.2

0.3

3.3

0.04

Arida

5

> 50

150

-

Iyo

1.7

> 50

> 150

-

Karatsu

1.5

> 50

> 150

-

Susceptible strain

1.3

8.6

8.9

-

Data are from reference (6)

Toxicity to Beneficial Arthropods Table 5 shows the activity of pyflubumide on several species of beneficial arthropods and natural enemies. Pyflubumide was inactive against beneficial arthropods and natural enemies. This indicates that pyflubumide should be very safe for natural enemies, and consequently will fit well into IPM programs.

Toxicological Properties Table 6 shows some toxicological features of pyflubumide. These results suggest that pyflubumide is safe for mammals and fishes.



Table 5. Effects of pyflubumide on beneficial arthropods and natural enemies Common name

Scientific name

Silkworm

Bombyx mori

>100

Honey bee

Apis mellifera

>200

Hornfaced bee

Osmia cornifrons

>100

Predatory mite

Phytoseiulus persimilis

>200

Amblyseius californicus

>100

Amblyseius swirskii

>200

Lady beetle

Harmonia axyridis

>100

Predatory midge

Aphidoletes aphidimyza

>100

Parasite wasp

Apanteles glomeratus

>200

Encarsia formosa

>200

Predatory bug

Orius strigicollis

>100

Spider

Pardosa pseudoannulate

>200

LC30 (mg a .i. /L)

Table 6. Toxicological profile of pyflubumide Acute oral :

Rat LD50 female

>2000 mg/kg

Mutagenicity:

Ames test

Negative

Skin irritation:

Rabbit

No irritant

Aquatic organism:

Carp LC50

0.66 mg/L (96h)

Conclusions We have found that the carboxamides with specific fluoroalkyl groups showed acaricidal activity and the modification by referring to the structures of SDHI carboxamides and introduction of substituent on amide moiety finally led to discover pyflubumide. Pyflubumide possesses excellent acaricidal activity against spider mites of the genus Tetranychus and Panonychus. Resistant strains collected from the field are controlled as well. Pyflubumide has an excellent safety profile against various beneficial arthropods and natural enemies. Our results suggest that pyflubumide is not only an effective tool for controlling spider mites which had developed resistance to existing acaricides, but is also quite suitable for inclusion into IPM programs.


Acknowledgments The authors are very thankful to JPPA (Japan Plant Protection Association) and the national, prefectural and incorporated administrative agency research institutions for the technical supports and biological evaluations of pyflubumide.

References


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Synthesis and Biological Activity of a Novel Acaricide, Pyflubumide

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