Development of novel pesticides in the 21st century

© Pesticide Science Society of Japan 2020. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License (https://creativecommons.org/licenses/by-nc-nd/4.0/)

J. Pestic. Sci. 45(2), 54–74 (2020)DOI: 10.1584/jpestics.D20-201

Review Article

Development of novel pesticides in the 21st century

Noriharu Umetsu1,* and Yuichi Shirai2

1 Kibi International University, Department of Agriculture, Minami-Awaji, Hyogo 656–0484, Japan2 OAT Agrio Co., Ltd., Research and Development Division, Naruto, Tokushima 772–0021, Japan

(Received February 21, 2020; Accepted March 20, 2020)

General trends and strategies for novel pesticides are summarized. Global pesticide sales and pesticide discovery research are also briefly reviewed. At least 105 chemical pesticides have been launched during the past decade or are under development: 43 fungicides, 34 insecticides/acaricides, 6 nematicides, 21 herbicides, and 1 herbicide safener. Most of them are safe to humans and environmentally friendly. The most developed fungicides are SDHI (succinate dehydrogenase inhibitors), DMI (demethyl-ation inhibitors), QoI (quinone outside inhibitors), and QiI (quinone inside inhibitors). Due to the development of resistance to fungicides with existing modes of action, many fungicides possessing various novel modes of action have been launched or are under development. The trend of insecticide development is changing from organophosphorus, carbamate, and synthetic pyre-throids to nicotinic and diamide insecticides. During the past decade, compounds possessing a variety of novel modes of action have also been launched or are under development. Flupyradifurone and flupyrimin, exhibiting extremely low honeybee toxicity, have been developed and subjected to practical use. Herbicides possessing varied modes of action, such as acetolactate synthase, p-hydroxyphenylpyruvate dioxygenase, protoporphyrinogen oxidase, and very-long-chain fatty acid elongase inhibition, have been developed, but no herbicides possessing a novel mode action have commercialized in nearly 30 years. It is of interest that cyclopyrimorate, which was recently launched, and tetflupyrolimet, which is under development, have novel modes action: ho-mogentisate solanesyltransferase (HST) and dihydroorotate dehydrogenase (DHODH) inhibition, respectively. The development of useful acaricides and nematicides is also progressing. Some natural product origin pesticides are getting attention.

Keywords: novel pesticides, herbicide, fungicide, insecticide, acaricide, nematicide.

Introduction

Since the practice of agriculture began about 10,000 years ago in the Fertile Crescent of Mesopotamia, mankind has battled pests and diseases that threaten the sustainable food supply. The first recorded use of pesticides is about 4500 years ago by Sumeri-ans who used sulfur compounds to control insects and mites. The evolution of pesticides is classified into five single phases, namely, before 1000: early pest management; 1000–1850: use of plant, animal, or mineral derivatives; 1850–1940: use of inor-ganic products and industrial by-products; 1940–1970: use of synthetic organic compounds; 1970-present: use of lower-risk synthetic organic compounds.1) When organic chemistry was introduced to the pesticide science field after World War II, the door of industrial pesticide science was opened. In the past cen-tury, many pesticide companies have been founded in Europe

and the USA, most of which were merged in the 21st century, and various kinds of pesticides have been launched throughout the world. The wave of pesticide science came to Japan, and Jap-anese-origin pesticides have been developed one after another from the late 20th to the early 21st century. Currently, the pesti-cide production ability in Japan ranks topmost in the world.

The development and manufacture of effective, safe to hu-mans, and environmentally friendly pesticides have been a chal-lenge to feed the growing population of our planet. The develop-ment of pesticides that pose a lower risk to natural enemies and useful organisms and are compatible with IPM (Integrated Pest Management) was also an important target. In March 2018, a book titled Trend in Pesticide Discovery Research-Development of Safer and Environmentally Friendly Pesticides,2) overviewing pesticide discovery research with insecticides, acaricides, nema-ticides, fungicides, herbicides, natural-origin pesticides, biopes-ticides, and others in the world during the past decade, was pub-lished by the CMC Publishing Co. In the book, which was edited by one of the authors of the current manuscript, 43 Japanese and Chinese pesticide scientists gave an overview of the trends in pesticide discovery research in their area of expertise from around 2009 to the end of 2017. Since significant progress has been made in pesticide discovery research after publication of the book, the contents of the pesticide discovery research, in-cluding the progress until early 2019, have been summarized as

* To whom correspondence should be addressed. E-mail: [email protected] Published online April 24, 2020

https://creativecommons.org/licenses/by-nc-nd/4.0/

Vol. 45, No. 2, 54–74 (2020) Development of Novel Pesticides in the 21st Century 55

a series of commentary articles.3–8)

This manuscript is an attempt to summarize the overall trends in research, development, and commercialization of safer and environmentally friendly pesticides from around 2009 until early 2020 on the bases of the information on pesticide discov-ery research contained in the above book, the commentary ar-ticles, and the latest information thereafter.

1. General trends and strategies for novel pesticides

Since the appearance of synthetic organic pesticides, the de-velopment strategy for creating new pesticides has been as fol-lows9): (1) development of pesticides that are effective at an extremely low dosage, (2) development of pesticides that are readily degradable and less residual in the environment, and (3) development of selective toxic agrochemicals. The first strategy resulted in a remarkable decrease in the active ingredient re-quired for the control of pest insects, fungi, mites, nematodes, and weeds and eventually brought about a reduction in the load of pesticides to the environment. The second strategy realized the remarkable lowering of pesticide residue levels in crops and the environment. The third strategy to seek a compound that is effective in targeting only organisms such as insects, fungi, mites, nematodes, and weeds, but not toxic against non-target organisms such as humans and beneficial organisms, was a tool for finding safer and environmentally friendly pesticides. These development strategies have become increasingly prominent.

The amount of active ingredient applied per unit area in the 1930s–1950s was high, about 1 to 10 kg/ha for ingredients such as DNOC, thiuram, and DDT. Therefore, the environmental im-pact was relatively large. However, since then, many pesticides that exhibit efficacy in a smaller amount have been developed, and the application rate per unit area has significantly decreased.

Currently, there are not a few pesticides showing efficacy at 10 g or less/ha. As a result, the environmental impact of pesticides has been significantly reduced.

2. Global pesticide sales and pesticide discovery research

2.1. Sales of pesticide companies involved in pesticide discovery research worldwide

Figure 1 shows the 2016 and 2017 sales turnover of major pesti-cide companies worldwide10,11) with acquisition and merger in-formation. The company with the highest sales is Chem China, which acquired Syngenta, the sales turnover being $10,041 M in 2016. In second place was Bayer, but now ranks first in sales since it acquired Monsanto, followed by Corteva Agriscience (Dow AgroSciences and DuPont merged) and BASF. In fifth place is UPL, which recently acquired Arysta LifeScience. In ninth place is Sumitomo Chemical, a Japan-based pesticide company ($1,913 M). Sumitomo Chemical has recently acquired four South American subsidiaries, including a Brazilian subsid-iary of Nufarm,12) so the sales ranking of Sumitomo Chemical is likely to become higher. Many Japanese pesticide companies, such as Kumiai Chemical, Nihon Nohyaku, Nissan Chemical, and Ishihara Sangyo Kaisha, are very active in pesticide discov-ery research even though the size of the company is relatively small. Their sales turnover is shown separately in the lower left part of the figure.11)

2.2. Trends in global agrochemical patent activityIt is important to analyze the number of patent applications by global pesticide companies and research institutes as an in-dicator of pesticide discovery activities. According to Phillips McDougall,13) the number of patent applications for active pesti-

10,0419,478

6,1674,641

3,4962,8772,874

$m

DuPontAdama*

FMCNufarm

UPLSumitomo ChemicalArysta LifeScience

AlbaughRed Sun

Gowan

2,275

1,053527495

2,1322,0201,9131,816

SyngentaBayerBASF

Dow AgroSciences

Monsanto

Merger(CortevaAgriscience)

AcquisitionComplete onJune 2018

(Chem China)

0 2000 4000 6000 8000 10000

AcquisitionComplete on Feb. 2019

Kumiai Chemical: 537Nihon Nohyaku: 484Nissan Chemical: 452 ISK (Ishihara Sangyo Kaisha): 444Mitsui Chemicals Agro: 398Nippon Soda: 390

* transferred to Chem China

Sales in 2016 10) 2017 11)

9,6379,1026,421

Corteva 6,1383,8133,259

2,5312,3662,3352,4181,8971,270

Sales in 2017 11)

Note: Figure was reproduced with reference to the cited documents 10) and 11)

-

Fig. 1. World pesticide company sales.

56 N. Umetsu et al. Journal of Pesticide Science

cide ingredients with a priority date between 2008 and 2016 was 5,857. Of those, China accounted for 40% at 2,358, followed by Germany at 1,117, Japan at 706, the USA at 516, Switzerland at 487, and the Republic of Korea at 230. This suggests that pesti-cide discovery studies are actively carried out in these countries.

Table 1 shows the number of patent applications by company for 2008–2016.13) Of the total 3,298, Bayer had 638 applications and Syngenta 465, followed by BASF, Sumitomo Chemical, Cor-teva Agriscience (Dow+DuPont), and several other Japanese companies. In a case of patent applications by public institutions such as universities and research institutions (total 2,529), the top 10 are from China, such as the Chinese Academy of Agricul-tural Sciences (122), Nankai University (113), Zhejiang Univer-sity (95), the Chinese Agricultural University (82), and Nanjing Agricultural University (57). This suggests that pesticide dis-covery studies are actively conducted by public institutions in China.

2.3. General trends in novel pesticide discovery researchDuring the past decade, different kinds of chemical pesticides—fungicides, insecticides, nematicides, acaricides, and herbicides, as well as biopesticides—have been subjected to development. Chemical pesticides launched or under development during the past decade is total at least 105, and most of them are safe to humans and environmentally friendly: 43 fungicides, 34 insec-ticides/acaricides, 6 nematicides, 21 herbicides, and 1 herbicide safener. Though pesticide discovery studies based on genomic information or the structure–activity relationship and by chemi-cal biology have been actively conducted during the past decade, almost no products have been developed for practical use.

3. Fungicides

3.1. General trends in developmentThe fungicides for which ISO common name attached after 2010 are classified according to their mode of action and shown in

Table 2. General trends in fungicide development are as fol-lows.14) The first general trends in fungicide development are progress in the development of three major fungicides. The most common is SDHI (succinate dehydrogenase inhibitors) or those considered to be SDHI due to their chemical structure charac-teristics. SDHIs have become one of the largest groups of agri-cultural fungicides, as well as DMI (demethylation inhibitors) and inhibitors of the mitochondrial electron transport chain

Table 1. Number of patent applications by company from 2008–2016

Applicant Number of published patents

Bayer CropScience 638Syngenta 465BASF 459Sumitomo Chemicala) 219Dow AgroSciencesb) 196

303DuPontb) 107Nippon Sodaa) 85Sinochem 85Ishihara Sangyo Kaishaa) 46Nissan Chemicala) 45Others 953

Total 3,298a) Japanese company. b) Currently Corteva Agriscience.

⎫ ⎬ ⎭

Table 2. ISO common names of fungicides attached after 2010 and their mode of actiona)

Year Month ISO common name Mode of action

2010 1 Fluxapyroxad SDHIPyriofenone Unknown

7 Fenpyrazamine SBI2011 7 Benzovindiflupyr SDHI2012 3 Isofetamid SDHI

Tolprocarb MBI-P5 Coumoxystrobin QoI

Enoxastrobin QoIFenaminstrobin QoIFlufenoxystrobin QoIPyrisoxazole DMITriclopyricarb QoI

7 Oxathiapiprolin OSBPIPyriminostrobin QoI

2013 4 Mandestrobin QoIPicarbutrazox Unknown

2014 10 Dipymetitrone UnknownPyraziflumid SDHI

2015 4 Pydiflumetofen SDHI2016 4 Ipfentrifluconazole DMI

Mefentrifluconazole DMIQuinofumelin Unknown

7 Dichlobentiazox Unknown8 Fenpicoxamid QiI

2017 3 Fluindapyr SDHIIsoflucypram SDHI

4 Aminopyrifen GWT-1Inpyrfluxam SDHI

9 Pyrapropoyne SDHIb)

11 Florylpicoxamid QiIc)

Fluopimomide UnknownIpflufenoquin UnknownMetyltetraprole QoIPyridachlometyl Unknown

2018 10 Fluoxapiprolin OSBPId)

a) Revised based on the latest information in the table published in Ref. 14. b) Compounds that have not been reported to be SDHI, but seem to be SDHI in chemical structure. c) Compounds that have not been re-ported to be QiI, but seem to be QiI in chemical structure. d) Compounds that have not been reported to be OSBPI (Oxysterol Binding Protein In-hibitors), but seem to be OSBPI in chemical structure.


complex III, i.e., QoI (quinone outside inhibitors) and QiI (qui-none inside inhibitors) (see Fig. 2). The SDHI acts on complex II of the mitochondrial electron transport chains, as shown in Fig. 2. Although the number of developed SDHIs has become comparable to those of DMI and QoI, post-SDHI fungicides are now desired due to successive reports on fungal pathogen re-sistance to existing SDHIs. DMIs, sterol biosynthesis inhibitors of the cell membrane typified by a triazole fungicide, continue to play an important role in controlling plant diseases due to their broad spectrum, high therapeutic effect, and relatively slow development of resistance. Therefore, the development of a few, if not all, new DMI fungicides is in progress in response to the appearance of resistance to existing DMIs and the fact that many important DMIs are listed in the compounds suspected to have endocrine disrupting effects in Europe. As a QoI fungicide that acts at the quinone outside (Qo) site of the inner membrane of complex III, 10 compounds have been developed since 2010. As a QiI fungicide that acts at the quinone inside (Qi) site of the inner membrane of complex III, two compounds have been de-veloped since 2010.

The second general trend is the development of fungicides with a novel mode of action and a unique chemical structure. Those with a completely new mode of action as agricultural fun-gicides and those with unique chemical structures are being de-veloped.

Other trends are the development of novel plant defense acti-vators and novel natural product origin fungicides.

3.2. Recently launched or under development3.2.1. SDHI fungicides

Table 3 shows information on 17 SDHI fungicides that were de-veloped after 201014,15) except for boscalid which was launched in 2003. Penthiopyrad (Affet® SC, Gaia® WDG) by Mitsui Chemicals Agro, isofetamid (Kenja®) by Ishihara Sangyo Kaisha, pyraziflumid (Parade®) by Nihon Nohyaku, and inpyrfluxam (Indiflin™) by Sumitomo Chemical have already been marketed.

Pyrapropoyne is under development by Nissan Chemical.Isofetamid was registered in December 2014 in Canada, in

July 2015 in the USA, and in November 2017 in Japan. It has broad-spectrum antifungal activity against Ascomycota (such as Botrytis spp., Sclerotinia spp., Monilinia spp., and Venturia spp.) and Deuteromycota (such as Alternaria spp. and Mycovellosiel-la spp.) and is effective against existing SDHI-resistant patho-gens.16,17)

Pyraziflumid acquired registration in Japan in 2018. It is a versatile fungicide applicable to a wide range of crops such as rice, horticulture products, and turf. It has a pyrazine carbox-amide skeleton.18,19)

Inpyrfluxam exhibits high efficacy against major plant dis-eases in the European region, such as brown rust on wheat, net blotch on barley, and black scurf on potatoes.20)

Flubeneteram, which just obtained an ISO common name in early 2020,21) is an anilide fungicide and is considered to be an SDHI based on its chemical structure.

Among multinational agrochemical manufacturers, one com-pany has multiple SDHI fungicides15) and is trying to separate the compounds by usage method and target crops in response to the characteristics of the compounds. As an example, Syngenta developed four SDHI fungicides. Isopyrazam (Reflect®) is for foliar application to control rust and net blotch of wheat. Sedax-ane (Vibrance®) is a seed-treatment fungicide for wheat, beans, and potatoes. Benzovindiflupyr (Solatenol™) is a rust-control fungicide for soybeans. Pydiflumetofen (Adepidyn™) is for the control of powdery mildew and Alternaria disease of vegetables, fruit trees, etc., as well as wheat leaf blight and wheat scab.22)

Bayer launched bixafen (Aviator® Xpro™, Siltra® Xpro™, etc.), penflufen (EverGol® Prime), and fluopyram (Luna®). Iso-flucypram, under development by Bayer, exhibits efficacy for the control of leaf spot diseases on a large range of crops.23)

3.2.2. Inhibitors of the mitochondrial electron transport chain complex III

A total of 12 compounds have been launched or are under de-

Fig. 2. Model for electron transport chain in the mitochondria, and action point of SDHI, QoI and QiI.


Pyribencarb Picoxystrobin Mandestrobin

Metyltetraprole

Coumoxystrobin(SRICI)

Enoxastrobin(SRICI)

Flufenoxystrobin(SRICI)

Pyriminostrobin(Shenyang Sciencreat Chemicals)

Triclopyricarb(SRICI)

Fenaminstrobin(SRICI)

Fig. 3. (a) Chemical structures of four QoI fungicides. (b) Chemical structures of six QoI fungicides under development by Chinese companies.

Table 3. Recently launched or under development SDHI fungicidesa)

NN

F3C O

NH

S

Chemical structures

Common nameCompany nameRegistration year

Chemical structures


Chemical structures


BoscalidBASF2003

PyrapropoyneNissan ChemicalUnder development

Isoflucypramb)

Bayer Under development

PenthiopyradMitsui Chemicals Agro2009

Flubeneteramb)

Dongguan Hec TechUnder development

IsopyrazamSyngenta2010

IsofetamidIshihara Sangyo Kaisha2015

Fluxapyroxad (Xemium®)BASF2011

SedaxaneSyngenta2011

PyraziflumidNihon Nohyaku2018

BixafenBayer2011

Benzovindiflupyr Syngenta2012

Fluindapyrb)

Isagro/FMCUnder development

PenflufenBayer2011

PydiflumetofenSyngenta2016

Inpyrfluxam Sumitomo Chemical2019 (Sept.)

FluopyramBayer2012

NN

HF2C O

NH N

O

N

Cl

NN

HF2C O

N

FCl

NN

HF2C O

NH

NN

HF2C O

NH

NN

F F

NH

O

O

CF3

Cl

SO

NH O

ON

N

HF2C O

NH

FF F

CF3 O

NH

N

Cl CF3

NN

HF2C O

NH

ClCl

NN

HF2C O

NH

ClCl

FO

NH

NN

CF3

FF

O

NH

N

Cl

Cl

NN

O

NH

FN

N

HF2C O

NCl

Cl

O

Cl

NN

HF2C O

NH

F

NN

HF2C O

NH

a) Partially modified and added new molecule to the Fig. 3 of Ref. 15. b) Compounds considered to be SDHI based on chemical structure.


velopment as inhibitors of the mitochondrial electron transport chain complex III since 2010,14) their chemical structures being shown in Figs. 3(a), 3(b), and 4. Of them, 10 compounds are QoI fungicides.

Pyribencarb (K-I Chemical Research Institute and Kumiai Chemical) was registered in 2012 in Japan (Trade name: Fanta-sista® GWP, Fanbell® GWP). It is a novel benzyl carbamate-type fungicide against a wide range of plant pathogenic fungi, espe-cially gray mold and stem rot.24) Though pyribencarb belongs to QoI group, it is active against strobilurin-resistant fungi.

Picoxystrobin (Acanto®, Syngenta) was discovered by Syngen-ta and transferred to DuPont in 2006. DuPont registered it in the USA in 2012. In Japan, Nihon Nohyaku marketed it in 2016 as a Major® Flowable.25) Picoxystrobin is a strobilurin fungicide (QoI inhibitor) effective against a wide range of diseases.

Mandestrobin (Sclea® flowable, Sumitomo Chemical), a stro-bilurin fungicide, was discovered by Shionogi & Co., Ltd., and commercially developed by Sumitomo Chemical. It is effective against sclerotinia rot, fruit tree scab, etc., with a low risk of phy-totoxicity.26,27) It was launched in 2016 in Japan and is under commercial development in many countries.

Metyltetraprole (Pavecto®, Sumitomo Chemical) is a new fungicide with a unique tetrazolinone moiety that is effective against pathogens resistant to existing fungicides. It is highly ef-fective against a wide range of fungal diseases, including impor-tant cereal diseases, such as wheat leaf blight. Sumitomo Chemi-cal is promoting development jointly with BASF in the EU, aim-ing to launch after 2022.28) Metyltetraprole is highly effective against QoI-resistant strains of various pathogen species.29,30)

Six QoI fungicides with ISO common names are currently under development by Chinese companies: coumoxystrobin,

enoxastrobin, flufenoxystrobin, triclopyricarb, and fenamin-strobin by SRICI and pyriminostrobin by Shenyang Sciencreat Chemicals (see structures in Fig. 3(b)).14) It is unclear wheth-er they aim to obtain registrations around the world, as well as what characteristics each QoI has and how to segregate each product in the market.

As QiI fungicides, two compounds are currently under devel-opment. Fenpicoxamid (Inatreq™, Meiji Seika Pharma, Dow; currently Corteva Agriscience), whose structure is shown in Fig. 4, is a conversion product of UK-2A isolated from the cul-ture broth of Streptomyces spp. by Ueki et al. at Osaka City Uni-versity, and its action is inhibition of the mitochondrial electron transport system complex III. Meiji Seika Pharma introduced UK-2A from the university and subjected it to joint develop-ment with Dow after converting its structure into fenpicoxa-mid.31) It is currently under development as an innovative fun-gicide for controlling key diseases in cereals, such as Septoria tritici and rust. It shows no cross-resistance to existing cereal fungicides.31,32) Fenpicoxamid is a propesticide, since it is con-verted to UK-2A in crops.

Florylpicoxamid (Adavelt™, Corteva Agriscience) is a neop-icolinamide fungicide under development and presumed to be a QiI, having the same mode of action as fenpicoxamid. Florylpi-coxamid controls a wide range of pathogens including Septoria spp., powdery mildew, Botrytis spp., Anthracnose, Alternaria, scab, Monilinia, and others.33)

3.2.3. DMI fungicidesCurrently, three DMIs are under development, and their struc-tures are shown in Fig. 5.14) Of these, mefentrifluconazole and pyrisoxazole should be noted. Mefentrifluconazole (Revysol®) is the first isopropanol azole discovered and developed by BASF. Its registration was approved in the EU in 2019. It is highly ef-fective against key fungal diseases in both row and specialty crops, including cereals, corn, soybeans, rice, grapevines, fruits, vegetables, and turf.34) Pyrisoxazole, developed by SRICI, is a pyridine-type DMI that is effective against Botrytis cinerea and tomato leaf mold. The development status for this fungicide out-

Flutianil Fenpyrazamine Picarbutrazox

Tebufloquin Pyriofenone Oxathiapiprolin

Tolprocarb Quinofumelin

Fig. 6. Chemical structure of the fungicides with novel or unknown mode of action.

R = Me; mefentrifluconazole iPr; ipfentrifluconazole Pyrisoxazole

Fig. 5. Chemical structures of DMI fungicides.

UK-2A Fenpicoxamid

Florylpicoxamid

Fig. 4. Chemical structures of QiI fungicide.


side China is unknown.3.2.4. Mode of action is novel or unknown

Eight fungicides with a novel or unknown mode of action and marketed or under development since 2010, is given based on the review by Fushikida14) and on other additional information. The chemical structures of these compounds are shown in Fig. 6.

Flutianil (Gatten® EC, OAT Agrio Co.) was registered in 2013 in Japan.35) Flutianil is chemically characterized as a cyanometh-ylene thiazolidine. It exhibits therapeutic and preventive effects against powdery mildew at a low dosage.36) The mode of action of this compound has not yet been reported.

Fenpyrazamine (Prolectus®, Pixio® DF, Sumitomo Chemi-cal) is a novel fungicide with an aminopyrazolinone structure that has shown high efficacy against gray mold, stem rot, and brown rot in field trials. The target enzyme of fenpyrazamine is the 3-keto reductase in the ergosterol biosynthetic pathway.37) Prolectus® was first launched in Italy in 2012, and Pixio® DF was launched in Japan in 2014.

Picarbutrazox (Pythilock®, Nae Fine®, Pisi Rock®, Nippon Soda) was registered in June 2017 in Japan.38) It belongs to the tetrazolyl oxime class, controlling oomycete diseases such as downy mildew and late blight. The mode of action of this com-pound is unknown, but it seems to have a new one, since the treatment of picarbutrazox causes swelling and hyperbranching of mycelia and inhibits zoospore formation, zoospore encyst-ment, and cystospore germination.39)

Tebufloquin (Try® flowable, Meiji Seika Pharma) was regis-tered in 2013 in Japan.14) It is used to control rice blast disease. The mode of action of this compound has not been clarified, but it is considered a respiratory inhibitor that acts on the mito-chondrial electron transport system.

Pyriofenone (Property® flowable, Ishihara Sangyo Kaisha) is a novel fungicide with a benzoyl pyridine structure and was registered in 2013 in Japan. It is very effective against powdery mildew on wheat, cucumbers, strawberries, and eggplants. It is of interest that pyriofenone is effective against QoI- and DMI-resistant fungal plant pathogens. The mode of action of this compound was reported to be inhibition of the formation of ap-pressoria and conidia and induction of morphological abnor-mality of the secondary appressorium and hyphae.40)

Oxathiapiprolin (Zorvec™, Orondis™, Corteva Agriscience) is a new class of piperidinyl thiazole isoxazoline fungicide.41) The US EPA approved it in 2015 for use against several fungal dis-eases, including downy mildew and late blight on crops such as vegetables, ornamentals, and turf. Its mode of action involves binding to the oxysterol-binding protein in Oomycetes.14,42) The practical spray concentration of this compound is about 20 ppm.

Tolprocarb (Sanblas®, Mitsui Chemicals Agro) is a rice blast fungicide registered in 2015 in Japan. Its mode of action was re-vealed to be inhibition of the polyketide synthase in the melanin biosynthesis pathway. In addition, tolprocarb induces systemic acquired resistance in Arabidopsis thaliana and rice. Owing to these double modes of action, tolprocarb can efficiently control not only rice blast but also bacterial diseases.43) Tolprocarb also provides long-term residual activity.

Quinofumelin (Mitsui Chemicals Agro) has new action char-acteristics. It effectively controls scabs, Botrytis cinerea, blast disease, and anthrax of fruits, vegetables, rape seeds, rice, etc. Mitsui Chemicals Agro signed a global license agreement with Bayer for its development and commercialization. They plan to apply for registration in 2020 in Japan and other countries.44,45)

3.2.5. OthersFour other fungicides, the structures of which are shown in Fig. 7, are currently under development. Dichlobentiazox (Kumi ai Chemical) is a novel fungicide that seems to be a plant defense activator created in the search for saccharin derivatives. It shows a stable effect against rice blast disease under various environmental conditions and treatment methods. It is also highly safe for rice seedlings with nursery box treatment. It is scheduled to launch in 2020.46)

Aminopyrifen (Agro-Kanesho) is a novel fungicide, and its synthesis and structure activity relationships were recently re-ported.47) It is reported that aminopyrifen inhibits the GWT-1 protein in glycosylphosphatidylinositol-anchor biosynthesis.48)

Dipymetitrone (Bayer) is a novel fungicide under develop-ment that is effective against Phytophthora rot, downy mildew, scab, early blight, and Botrytis cinerea.21,49) The mode of action is unknown.

The ISO common name of fluoxapiprolin (Bayer) was granted in October 2018.21) It is effective against Phytophthora rot and downy mildew. It seems to be in the same group of fungicides as oxathiapiprolin, under development by Corteva Agriscience.

4. Insecticides

4.1. General trendsIn the history of insecticide development, trends have changed from organophosphates, carbamates, and synthetic pyrethroids to nicotinic and diamide insecticides.50) In recent years, com-pounds that are not classified into nicotinic and diamide insec-ticides and have or seem to have a variety of novel modes of action have been under development. This is useful in terms of resistance management.

Table 4 shows the major insecticides categorized into nico-tinic, diamide, and other novel insecticides that were launched

Dichlobentiazox Aminopyrifen Dipymetitrone

Fluoxapiprolin

Fig. 7. Chemical structure of other fungicides.


or under development after 2010. Four nicotinic insecticides, such as flupyrimin and triflumezopyrim, are on the market. As diamide insecticides, four compounds, such as cyantraniliprole and tetraniliprole, are on the market or under development. As other novel insecticides, nine insecticides, such as pyrifluquinaz-on, flometoquin, fluxametamide, broflanilide, and afidopyropen, will be mentioned below. The outline of each group of insecti-cides is also described below.

4.2. Trends in nicotinic insecticidesNicotinic insecticides, which originate from nicotine, act on nic-otinic acetylcholine receptors (nAChRs) and are effective against a wide range of pests at low doses; these made up about 23% of the global insecticide market in 2016. Nicotinic insecticides are classified into “first generation” (nicotine, anabasine), “second generation” (imidacloprid, thiacloprid, nitenpyram, clothiani-din, acetamiprid, thiamethoxam, dinotefuran), and “third gen-eration” (sulfoxaflor, flupyradifurone, flupyrimin, triflumezopy-

rim, dicloromezotiaz), which were launched or under develop-ment after 2010.50,51) Some nicotinic insecticides of the second generation have been regarded as toxic to some non-target organisms, especially honeybees, and the use of three agents is prohibited in the field in the EU.

Figure 8 shows the structure of nicotinic insecticides and their honeybee toxicity information.4) Due to the potential hon-eybee toxicity problem, the use of imidacloprid, clothianidin, and thiamethoxam was prohibited in the EU as a preventive measure in April 2013 and officially banned for use outdoors in 2018.

Regarding sulfoxaflor (Isoclast™), which is classified as sulf-oximines, the US EPA banned its use in March 2016 due to the lack of honeybee toxicity data based on the outcome of a trial involving a beekeeper’s organization (the EPA lost). However, it was re-registered in February 2017. Sulfoxaflor shows a stable effect against sucking pests, especially stink bugs and scales, and was registered in Japan in November 2017.

Table 4. Insecticides marketed or under development since 2010a)

Nicotinic insecticidesNeonicotinoids before 2009 imidacloprid, acetamiprid, clothianidin, dinotefuran, nitenpyram, thiacloprid, thiamethoxam,

cycloxaprid, paichongding (Both marketed in China)after 2010 flupyrimin (Registered in USA in 2018, in 2019 in Japan)

Sulfoximine sulfoxaflor, Registered in 2017Butenolides flupyradifurone, Registered in 2015Mesoionics triflumezopyrim, dicloromezotiaz, Both registered in 2018

Diamide insecticides before 2009 flubendiamide (Registered in 2007), chlorantraniliprole (2009)after 2010 cyantraniliprole (Registered in 2014), cyclaniliprole (2017), tetraniliprole (under development)

cyhalodiamide, tetrachlorantraniliprole (Both under development in China)

Insecticides other than nicotinic and diamide insecticides possessing novel or unknown mode of actionRegistered pyrifluquinazon (Registered in 2010), flometoquin (2018), fluxametamide (2019)Under development broflanilide, benzpyrimoxan, afidopyropen, tyclopyrazoflor, oxazosulfyl, spiropidion, isocycloseram,

dimpropyridaza) Registered year: Unless otherwise noted, the year of registration in Japan.

Fig. 8. Structure of nicotinic insecticides and honeybee toxicity.


Flupyradifurone (Sivanto™), which is classified as butano-lides, was registered in the USA and Japan in 2015. It is assumed to be harmless to honeybees, although like neonicotinoids, it binds to nAchRs. It was shown that flupyradifurone can reduce taste and appetitive learning performance in honeybees foraging for pollen and nectar, although only the highest concentration had significant effects.52)

Flupyrimin, which is classified as neonicotinoids, was reg-istered in Japan in 2019 (trade name: Lydia Granules, Emilia Flowable) and exhibits remarkable biological properties featur-ing outstanding potency to neonicotinoid-insensitive rice insect pests and superior safety toward pollinators. Intriguingly, flupy-rimin acts on the insect nAChRs as an antagonist via a recogni-tion manner different from those of the other nicotinic insecti-cides.53)

Triflumezopyrim (Pyraxalt™) and dicloromezotiaz belong to the novel class of mesoionic insecticides and have already been commercialized.54) Triflumezopyrim provides outstanding con-trol of hoppers, including the brown planthopper, which is al-ready displaying resistance to neonicotinoids such as imidaclo-

prid.55) Dicloromezotiaz shows excellent efficacy against a broad range of lepidopteran pests. It binds to the orthosteric site of the nicotinic acetylcholine receptor but acts primarily via inhibition of the binding site and leads to lethargic poisoning among dif-ferent insect species.56)

Though the IRAC classification is not described, research and development of nicotinic insecticides by Chinese institu-tions are ongoing, and cycloxaprid, paichongding, guadipyr, and cycloxylidin (see structures in Fig. 9) have been developed as insecticides in China.51) The status of the development of these nicotinic insecticides outside China is unknown. Cycloxaprid, developed by East China University of Science and Technology, shows outstanding activity against a variety of homopteran and lepidopteran pests and lacks cross-resistance in comparison with traditional neonicotinoids.57) It acts on insect nAChRs but has different binding sites than that of imidacloprid.

Table 5 summarizes the honeybee toxicity data for these nico-tinic insecticides.4) Oral and contact toxicities to honeybees are generally low or relatively low for the nicotinic insecticides ex-cept for the three compounds banned in the EU. Among them, the contact toxicity of thiacloprid is about 1/800 that of imida-cloprid. The recently marketed flupyradifurone and flupyrimin (Fig. 8) have even lower honeybee toxicities. Selective toxic in-secticides were developed using honeybee toxicity as an index.

4.3. Trends in diamide insecticidesTable 6 shows the development history of diamide insecticides.4) Nihon Nohyaku developed flubendiamide and obtained reg-istration in 2007, and this was followed by DuPont’s chloran-traniliprole. After 2010, cyantraniliprole, cyclaniliprole, tetra-niliprole, cyhalodiamide, and tetrachlorantraniliprole followed. Chlorantraniliprole and cyantraniliprole, which were originally developed by DuPont, were recently transferred to FMC. These compounds have a novel mode of action, acting on ryanodine receptors, and because of their excellent control performance,

CycloxapridEast China University of Science and Technology

PaichongdingEast China University of Science and Technology

GuadipyrChinese Agricultural University

Cycloxylidin Wuhan Institute of Technology

Fig. 9. New nicotinic insecticides for development in China.

Table 5. Honeybee toxicity data for nicotinic insecticides

Compound Oral LD50 (µg/bee) Contact LD50 (µg/bee)

Imidacloprid (Admire), Bayer 0.004a) 0.0179b)

Clothianidin (Dantotsu), Sumitomo Chemical 0.004a) 0.0218b)

Thiamethoxam (Actara), Syngenta 0.005a) 0.0299b)

Dinotefuran (Starkle), Mitui Chemicals Agro 0.02a) 0.075b)

Acetamiprid (Mospilan), Nippon Soda 14.5a) 7.07b)

Thiacloprid (Bariard), Bayer — 14.6b)

Nitenpyram (Bestguard), Sumitomo Chemical — 0.138b)

Sulfoxaflor (Transform, Closer), Dowc) 0.146d) 0.379d)

Flupyradifurone (Sivanto), Bayer 1.2e) 122.8e)

Flupyrimin, Meiji Seika Pharma >53.6e) >100e)

Triflumezopyrim, DuPontc) 0.51e) 0.39e)

a) www.pesticideresearch.com/site/?p=12101 : Flupyradifurone: A new insecticide or just another neonicotinoid? b) S. Iwas, Agchem age, 190 (2008). c) Currently Corteva Agriscience. d) ISOCLAST Active Technical Bulletin; 0901b803808fd73f. e) Ref. 51.


particularly with lepidopteran pests, they can be used in a wide range of crop-protection situations. In 2016, three diamide in-secticides, flubendiamide, chlorantraniliprole, and cyantranilip-role, together accounted for 11.5% of the $16.46 billion global insecticide market.

Cyclaniliprole (Teppan®), which was registered by Ishihara Sangyo Kaisha in Japan in 2017, is highly effective against lepi-dopteran pests as well as hemipteran pests such as thrips, white-fly, and tea green leafhopper.58,59)

Tetraniliprole (Vayego™),60) cyhalodiamide, and tetrachloran-traniliprole4) are currently under development. In addition, many companies and universities have applied for patents for di-amide insecticides. However, the number of patent applications has recently been declining, and discovery research for diamide insecticides seems to have settled down.50)

4.4. Trends in novel insecticides other than nicotinic and diamide insecticides

An overview of the 11 insecticides other than nicotinic and di-amide insecticides that were launched or are under development after 2010 is described based on Suwa and Nakano’s review50) and on other recent information. Figure 10 shows the chemical structures of these 11 insecticides and their related compounds.

Pyrifluquinazon (Colt®, Nihon Nohyaku) is an insect be-havior control agent (to halt insect feeding so that they starve) for tea, vegetables, and fruit trees that was registered in Japan in 2010. It also shows a good effect on Bemisia tabaci (tobacco whitefly), biotype Q.50,61)

Flometoquin (Finesave®, Nippon Kayaku and Meiji Seika Pharma), an insecticide with a quinoline skeleton, was registered

in Japan in March 2018.62) It is effective to control Lepidoptera, Diptera, Hemiptera, and mites. Applicable crops are fruit trees, vegetables, etc. It inhibits the electron transport system.

Fluxametamide (Gracia®, Nissan Chemical), an isoxazoline compound, was discovered and has been developed, being reg-istered in January 2019 in Japan. The site of action is GABA: γ-aminobutyric acid (GABA Cl−, Glu Cl−channel inhibitor). The characteristics of fluxametamide include effectiveness against a very broad spectrum of important pests (Lepidoptera, Thy-sanoptera, Diptera, Acari, Coleoptera, and some Hemiptera). There is little influence on the bee-visiting insects.63,64)

Broflanilide (Vedira™, Tenebenal™, Mitsui Chemicals Agro), currently being jointly developed with BASF, has a unique chemical structure characterized as a meta-diamide and exhibits high activity against various pests, including lepidopteran, cole-opteran, and thysanopteran pests.65,66) Broflanilide received the first registration worldwide in Australia in January 2020. Bro-flanilide is metabolized to desmethyl-broflanilide, and it acts as a noncompetitive resistant-to-dieldrin (RDL) γ-aminobutyric acid (GABA) receptor antagonist. The binding site of desmethyl-broflanilide was demonstrated to be distinct from that of con-ventional noncompetitive antagonists such as fipronil.

Benzpyrimoxan (Orchestra® flowable, Nihon Nohyaku) is currently under development. It seems to be a next-generation planthopper and green rice leafhopper control insecticide.50) Benzpyrimoxan is highly active, specifically against the nymphal stages, and could act on nymphal molting as a kind of insect growth regulator (IGR). Its insecticidal activity against nymphs is much superior to that against other stages, with a unique symptom that is different from ones caused by other existing

Table 6. Development history of diamide insecticides

NH

O

NH

O

SO O

CF3

CF3F

I

ClN

NN

O

HN

HN O

NC

NN

NN

CF3

Br

ClN

NN

O

HN

HN O

Cl

NH

O

NH

O

CN

CF3

CF3F

Cl

Br

ClN

NN

O

HN

HN O

NC

Br

ClN

NN

O

HN

HN O

ClCl

Cl

Br

ClN

NN

O

HN

HN O

ClBr

a) Year of common name given. b) The product was transferred to FMC.


IGR products.67)

In 2017, the common name of oxazosulfyl included in the Sumitomo Chemical patent claims was released. While many patents were released from Sumitomo Chemical after that, Nihon Nohyaku, Syngenta, Bayer, Nippon Soda, Nissan Chemi-cal, Agro-Kanesho, Hokko Chemical, and BASF have also issued patents one after another and have become one of the major groups in recent insecticide-related patents.50) Oxazosul-fyl is characterized by its aryl ethylsulfonyl moiety and exhibits broad-spectrum control of insect pests, including Hemiptera, Coleoptera, and Lepidoptera.68) Since this compound group has a broad insecticidal spectrum, it can grow into a large group of insecticides as a highly versatile pest control agent.50)

A patent describing a compound having a pyridin-3-yl group was published by Bayer in 2009. After that, Dow, Sumitomo Chemical, Nissan Chemical, Syngenta, BASF, Mitsui Chemicals Agro, and DuPont continued to publish related patents. These

companies have been competing in exploratory research on this group of compounds.50) Among them, the common name ty-clopyrazoflor69) was released by Dow (Corteva Agriscience) in 2017. The basic activity of this compound group against aphids has already reached the same level as that of neonicotinoids, and useful insecticides may be created from this group in the near future.50)

Spiropidion (Syngenta) is a new tetramic acid family member (IRAC MoA group 23) insecticide and acaricide and is currently under development by Syngenta.70,71) It is regarded as an inhibi-tor of acetyl CoA carboxylase, disrupting fatty acid biosynthe-sis, and is presumed to show excellent activity against aphids, whiteflies, thrips, diamondback moths, and mites in vegetables and specialty crops. It has a favorable toxicological and environ-mental profile and, owing to its safety to pollinators and other non-target organisms, it is perfectly suitable for IPM practices.

Afidopyropen (Inscalis®, Meiji Seika Pharma) is a structur-

Pyrifluquinazon Flometoquin Fluxametamide

Broflanilide Benzpyrimoxan Oxazosulfyl

Bayer (WO2009149858) and Tyclopyrazoflor Spiropidion

Pyripyropene A (left) and Afidopyropen (right)

Isocycloseram Dimpropyridaz

Fig. 10. Chemical structures of 11 novel insecticides and their related compounds.


ally modified compound of pyripyropene A,72) an antibiotic obtained from the culture of Aspergillus fumigatus through col-laboration between the Kitasato Institute, Meiji Seika Pharma, and BASF.72,73) The circled parts in the chemical structure of afidopyropen in Fig. 10 are the structure conversion sites. The joint development company BASF applied for registration in the USA and Canada. Afidopyropen controls aphids, whiteflies, scales, and leafhoppers, being effective against pests that have acquired resistance to existing insecticides. It is presumed that afidopyropen acts on the chordotonal organ, an insect-specific hearing organ. Details of the development of this insecticide are described in Oyama’s review.74)

Isocycloseram (Syngenta) is a member of the isoxazoline class of insecticides.75) The ISO common name was given in June 2018. It is in the same family as fluxametamide from Nissan Chemical. Isocycloseram acts as a noncompetitive antagonist of the invertebrate GABA receptor.

Dimpropyridaz (BASF) is a new insecticide, the ISO common name being given in December 2018.21) It is a pyrazole carbox-amide insecticide that has a pyridin-3-yl group, as in tyclopyr-azoflor.50) Dimpropyridaz is effective against aphids.

5. Acaricides

5.1. General trends in acaricide developmentAlthough the types of acaricides seem to be numerous at first glance, the key acaricides have changed over time due to the development of resistance. Though there were only a limited number of modes of action for acaricides until the 1990s, acari-cides with various modes of action have been developed since the 2000s.76) The acaricides developed after 2000 are classified as “Inhibitors of the mitochondrial electron transport chain com-plex II,” “Acetyl CoA carboxylase inhibitors,” and “Acaricides possessing a novel mode of action or unknown mode of action.”

5.2. Trends in the development of inhibitors of the mitochondrial electron transport chain complex II

This class of acaricides started with a novel benzoyl acetonitrile acaricide, cyflumetofen (Danisaraba®), which was discovered by Otsuka Chemical (currently OAT Agrio) and registered in 2007 in Japan.76) Then cyenopyrafen (Starmite®, registered in 2008

by Nissan Chemical) and pyflubumide, a carboxyanilide acari-cide (Dani-Kong®, registered in 2017 by Nihon Nohyaku), were developed and marketed.76) The chemical structure of the three acaricides is shown in Fig. 11. All three acaricides are effective at all stages of spider mite development as inhibitors of the mi-tochondrial electron transport chain complex II. It is of interest that pyflubumide has the same mode of action as the other two acaricides, but the site of action is different, and cross-resistance is avoided.77) Cyetpyrafen (Sinochem), the ISO common name being given in 2020,21) is presumed to be an inhibitor of the mi-tochondrial electron transport chain complex II based on the similarity in chemical structure to cyenopyrafen.

5.3. Trends in the development of acetyl CoA carboxylase inhibitors

Three acetyl CoA carboxylase inhibitors have been developed and marketed since 2003.76) These acaricides act by inhibiting lipid biosynthesis. There are two tetronic acid classes, spirodi-clofen (Daniemon®, registered in 2003 in Japan) and spirome-sifen (Danigetter®, registered in 2007 in Japan), and a tetramic acid class, spirotetramat (Movento®, Ultor®, registered in 2012 in Japan). The above three acaricides were developed by Bayer (see the chemical structure in Fig. 11). The general character-istics of biological activity are the same for the three acaricid-es, and they are effective not only for spider mites but also for rust mites. Characteristics of above three acaricides are as fol-lows.76) Spirodiclofen is effective only against mites and has no systemic activity. Spiromesifen shows activity against both mites and whiteflies. It also has leaf penetration activity. Spirotetramat is effective not only for mites but also for sucking pests. It has phloem migration activity, and irrigation treatment into the soil is possible.76)

In addition to the above three acaricides, spiropidion, which was mentioned in the section on novel insecticides, exhibits acaricidal activity.70)

5.4. Trends in the development of acaricides possessing a novel or unknown mode of action

Three acaricides with a novel or unknown mode of action have been developed since 2010. Fluxametamide (Gracia®, Nissan

Cyflumetofen Cyenopyrafen Pyflubumide Cyetpyrafen Spirodiclofen

Spiromesifen Spirotetramat Acynonapyr Flupentiofenox

Fig. 11. Chemical structures of acaricides launched or under development after 2007.


Chemical) is an insecticide and acaricide. See item 4.4, “Trends in novel insecticides other than nicotinic and diamide insecti-cides”.

Acyonapyr (NA-89, Danyote®, Nippon Soda) has a charac-teristic azabicyclo ring in its structure76,78) and was registered in March 2019 in Japan. It is reported that acynonapyr acts on inhibitory glutamate receptors and disrupts neurotransmis-sion.78) It has a selective effect on spider mites of Tetranychus and Panonychus. The practical concentration of acynonapyr is 100–67 ppm, and its application is currently expanding into fruit, tea, vegetables, and flowering fields.

Flupentiofenox (Kumiai Chemical) is a new acaricide, the ISO common name being given in 2020.21) Other information, in-cluding the mode of action, is not available.

5.5. Trends in the development of non-chemically synthesized acaricides

Two non-chemically synthesized acaricides have been developed since 2010. Formulated oil (safflower oil and cottonseed oil 97%, RM1963K, Suffoil® emulsion) was registered in 2015 in Japan, jointly developed by OAT Agrio and RIKEN. It can be used at a relatively high dilution ratio of 300 to 500 times (compared to machine oil, etc.). The mode of action against spider mites is suf-focation by spiracle blockage of adults and larva, but at the same time, it inhibits larval escape behavior in eggs during hatching, thus exhibiting an egg-killing effect.5,79)

Polyglycerin fatty acid ester 82% (Fumon®, Nippon Kayaku) is a food additive and was registered in 2016 in Japan, having insecticidal, fungicidal, and acaricidal activities. Its only mode of action is spiracle blockage, and it can be sprayed at a high dilu-tion (×1,000), so the risk of phytotoxicity is relatively low.76)

6. Nematicide development

6.1. General trendsThe methods of controlling plant-parasitic nematodes are largely divided into fumigant (gas) treatments and non-fumigant (con-tact agent) treatments. Most nematicides exhibits control effect by entering the nematode body through the surface phospho-lipid membrane. Methyl bromide, a typical fumigant, had a wide range of effects and was widely used around the world because of its low cost. However, the use of methyl bromide had been abolished in developed countries by 2005 due to fears of ozone

depletion and groundwater pollution at the Montreal Protocol meeting in 1995.80) In recent years, pesticide manufacturers have been actively developing safer non-fumigants.

6.2. Trends in developmentThe nematicides launched or under development after 2010 are shown in Fig. 12 with their chemical structures.80) Fluopyram (Bayer and Nihon Nohyaku) was developed and marketed as an SDHI fungicide by Bayer, but it has been reported by Nihon Nohyaku that it also acts as a nematicide. Bayer marketed it as Velum™ granules and Verango®,81) Nihon Nohyaku as Nema-clean® granules (August 2017 in Japan).82) These are the first ne-maticides acting via complex II inhibition, thus selectively in-hibiting the nematode’s generation of cellular energy. The nema-ticide exhibits a high control effect on the root-knot nematode, root-lesion nematode, cyst nematode, and potato rot nematode. Residual activity is also very high.

Tioxazafen (NemaStrike™, Monsant (currently Bayer)) is a seed-treatment nematicide developed by Monsanto to provide consistent broad-spectrum control of nematodes in corn, soy, and cotton.83) Its structure has a disubstituted oxadiazole skel-eton, representing a new class of nematicides. Tioxazafen ob-tained EPA registration in May 2017. Its use started in 2018 in 45 states in the USA. It has a broad spectrum against parasitic nematodes of corn, soybeans, and cotton. It stays in the roots of the crop for up to 75 days during crop growth.80)

Fluazaindolizine (Reklemel™ active, Salibro®, Corteva Agri-science) is a new, highly effective, and selective product for the control of plant parasitic nematodes, and it is expected to be reg-istered in 2020.80,84) It has an excellent effect on the root-knot nematode and root-lesion nematode. Specificity for nematodes coupled with the absence of activity against the target sites of commercial nematicides suggests that fluazaindolizine has a novel mode of action.

Fluensulfone (Bayer and ADAMA Agricultural Solutions) is a new nematicide of the fluoroalkenyl thioether group that has an excellent effect on the root-knot nematode and significantly reduces environmental impact with low toxicity to non-target insects and mammals.85) It was registered in the USA under the trade name Nimitz® and in Israel in 2014 for fruits and vege-tables. In Japan, it was registered in April 2017 as Nemashot® granules by ADAMA Japan and SDS Biotech.80) Fluensulfone in-hibits development, egg-laying, egg-hatching, feeding, and loco-motion. Fluensulfone’s mode of action is distinct from those of other currently available nematicides.85)

Cyclobutrifluram (Syngenta), the ISO common name being given in 2020,21) is presumed to be an inhibitor of the mitochon-drial electron transport chain complex II based on its similarity in chemical structure to fluopyram.

Nemguard (NEMguard®, Ecospray) is a non-chemically syn-thesized nematicide. Nemguard is a registered soil-applied ne-maticide based on garlic extract. It contains biologically active ingredients such as allicin and polysulfides derived from garlic concentrate. In addition to nematicidal and insecticidal prop-

Fluopyram Tioxazafen Fluazaindolizine

Fluensulfone Cyclobutrifluram

Nemguard(Garlic Extract)

Fig. 12. Chemical structure of new nematicides.


erties, the active ingredient also has fungicidal properties.86) In Italy, NEMguard WF has been registered for use on a range of crops, including carrots, potatoes, and tomatoes.

7. Herbicides

7.1. General trendsSince the 1940s, a large number of herbicides with different modes of action have been developed and provided for com-merce use. Figure 13 shows the history of the discovery of her-bicides with different modes of action, which can be roughly divided into pre-1980, the 1980s, the 1990s, and after 2018. The history of herbicide development by age group is described below based on the review by Tamai et al.87) and the latest infor-mation thereafter.

7.2. Research on the mode of action of old-fashioned herbicides7.2.1. Before 198087)

The discovery of the auxin action of 2,4-D (2,4-dichloro-phenoxyacetic acid), whose basic chemical structure is phenoxy-acetic acid, in 1942 led to the discovery of a selective herbicidal effect on broadleaf weeds in 1944. From 1956 to 1975, the mode of action of urea, triazine, and triazinone photosynthesis inhibi-tors was elucidated. In the 1970s, the mode of action of auxin transport inhibitors (naptalam), cell wall synthesis inhibitors (dichlobenil), microtubule polymerization inhibitors (triflura-lin), and dihydropteroate (an intermediate in folate biosynthesis) synthesis inhibitors (asulam) was revealed.

7.2.2. From the 1980s to the 2000s87)

In 1980, it was revealed that the action point of pyridazine herbicides on the carotenoid biosynthesis pathway was phy-toene desaturase (PDS). From 1982 to 1986, the site of action of phosphinothricin, the active form of glufosinate and bi-alaphos, was determined to be glutamine synthase (GS). From 1986 to 1989, it was clarified that the action point of diphenyl ether and phthalimide herbicides on the porphyrin biosynthetic pathway was protoporphyrinogen IX oxidase (PPO). In 1984, it was found that the action point of sulfonylurea herbicides and imidazolinone herbicides on the branched-chain amino acid synthesis pathway is acetolactate synthase (ALS), and the

action point of glyphosate on the aromatic amino acid biosyn-thesis pathway is 5-enolpyruvylshikimate phosphate synthase (EPSPS). From 1992 to 1993, it was clarified that the action point of triketone herbicide, represented by sulcotrione, was 4-hydroxyphenylpyruvate dioxygenase (HPPD). A long-term study from 1993 to 2000 clarified that the action point of chlo-roacetamide herbicide, which had not been elucidated for many years, is the very-long-chain fatty acid elongase (VLCFAE). Since 2000, VLCFAE-inhibiting herbicides have been developed in addition to ACCase-, ALS-, HPPD-, and PPO-inhibiting her-bicides.

7.2.3. After 2018There were no reports on herbicides with a novel mode of action for approximately 30 years after the launch of clomazone (DXP inhibitor in the MEP pathway) in the late 1980s until 2017.87) However, three herbicides possessing new modes of action have recently appeared. First, it was clarified that the site of action of the herbicide cinmethylin, whose registration has expired (in Japan), is fatty acid thioesterase (FAT).88) The second her-bicide is cyclopyrimorate. It has been reported that the site of action of this new herbicide, discovered by Mitsui Chemicals Agro and registered in Japan in September 2019, is the homo-gentisate solanesyltransferase (HST).89) The third one is a new herbicide, tetflupyrolimet, discovered by FMC. It was recently reported that tetflupyrolimet interferes with de novo pyrimidine biosynthesis via the inhibition of dihydroorotate dehydrogenase (DHODH).90)

7.3. Herbicides developed after 2008The herbicides launched or under development after 2008 will be described based on the review by Tamai et al.87) summarizing the herbicide discovery studies up to 2017 and on the latest in-formation as of January 2020. Since ACCase-, PDS-, and photo-synthesis inhibitors have not been developed during this period, the description of these herbicides has been omitted.

7.3.1. ALS inhibitorsALS-inhibiting herbicides include sulfonylureas, triazolinones, triazolopyrimidines, pyrimidinylsalicylic acids, imidazolinones, and sulfonanilides. The number of ALS inhibitors being devel-oped has been decreasing due to the problem of weed resistance to ALS inhibitors, and little discovery research has been con-ducted recently.87)

Table 7 shows the chemical structures, common names, com-pany name, group names, registered year, target crops, and dos-ages of ALS inhibitors. Recently developed sulfonylurea ALS in-hibitors include propyrisulfuron (Zeta-One®) from Sumitomo Chemical91) and metazosulfuron (Altair®) from Nissan Chemi-cal.92) Both herbicides have been developed for paddy rice and are characterized by their effectiveness against broadleaf weeds and Cyperaceous weeds, as well as against barnyard grass, which is difficult to control with conventional sulfonylurea herbicides.

The other two are pyrimisulfan (Best Partner®) and tria-famone, which are sulfonanilides. Pyrimisulfan, developed by Kumiai Chemical, has provided outstanding efficacy against

Fig. 13. History of herbicide development and mode of action studies.


major weeds of Japanese paddy fields, such as Echinochloa spp., Schoenoplectus juncoides, Monochoria vaginalis, and Lindernia spp. Pyrimisulfan is the first one-shot herbicide for rice con-taining only one active ingredient, with an original formula-tion technology.93) In addition, it can control other troublesome weeds, including Sagittaria trifolia, Scirpus nipponicus, Bolbos-choenus maritimus, Eleocharis kuroguwai, and sulfonylurea-resistant weeds, which have presented serious problems in re-cent years.

Triafamone (Council™ Complete (triafamone+tefuryltrione), etc.), developed by Bayer, is an herbicide for paddy rice and is highly effective against grass weeds, such as barnyard grass, as well as Cyperaceous weeds.94)

7.3.2. HPPD inhibitorsHPPD-inhibiting herbicides represent the most actively re-searched field, and many are being developed. They include trik-etones, pyrazoles, isoxazoles, and other bicyclo ring-type com-pounds. In addition, Bayer published a patent in 2011 for an HPPD inhibitor characterized by an amide structure. Syngenta published a patent in 2013 for an HPPD inhibitor characterized by a pyridazinone ring.87)

Table 8 shows information on various HPPD inhibitors. The triketone herbicides include tefuryltrione (Mighty-One®), fen-quinotrione (Effeeda®), and lancotrione-sodium (Promise®1 kg GR), launched in 2010, 2018, and 2019, respectively. Tefuryl-trione, developed by Bayer, is effective against sulfonylurea-tolerant weeds as well as annual and perennial weeds belonging to the Cyperus microiria Steud family.95) Fenquinotrione, devel-oped by Kumiai Chemical, shows excellent control against pre/post-emergence ALS-resistant broadleaf weeds under flooded conditions.96,97) It shows high safety to high-yield rice varieties for feed equal to or better than rice varieties for food. Lancot-

rione-sodium, registered in Japan in 2019 by Ishihara Sangyo Kaisha, is for paddy rice.7)

Bicyclopyrone, a bicyclo ring-type HPPD inhibitor, is an up-land herbicide developed by Syngenta. It shows a broad herbi-cidal spectrum against grass weeds and broadleaf weeds before and after emergence.87)

Tolpyralate (Brucia® flowable), a pyrazole-type HPPD inhib-itor, is a foliar spray herbicide for corn developed by Ishihara Sangyo Kaisha. It shows a high level of activity against a wide range of unwanted weeds, not only broadleaf weeds but also grasses.98)

7.3.3. PPO inhibitorsThe PPO-inhibiting herbicides inhibit protoporphyrinogen-IX oxidase (PPO), which catalyzes the oxidation of protoporphy-rinogen to protoporphyrin in the process of synthesizing the porphyrin ring. Inhibition of this enzyme ultimately results in pigment degradation and leaf necrosis, causing the plant to die. In recent years, the number of patent applications related to PPO-inhibiting herbicides has been declining.

Table 9 shows information on three PPO-inhibiting herbi-cides, tiafenacil (Dongbu Hannong Chemical), trifludimoxazin (BASF), and cyclopyranil (Kyoyu Agri), that have been in de-velopment since 2008.87) Trifludimoxazin (Tirexor™), currently under development by BASF, is a low-use-rate herbicide, from 12 to 50 g a.i./ha, that provides control of difficult-to-control weeds such as palmer amaranth and Kochia.99) It was designed to be active against existing PPO-resistant weeds, resulting in the broad-spectrum pre- and post-emergence herbicide.100)

7.3.4. VLCFAE inhibitorsThe VLCFAE-inhibiting herbicides had been primarily chloro-acetamides and oxyacetamides, but various skeletons have been identified since then. Very few patents for VLCFAE inhibitors

Table 7. ALS-inhibiting herbicides


have been published since 2008, and their skeletons are based on pyroxasulfone.

Table 10 shows information on four VLCFAE-inhibiting herbicides. Pyroxasulfone (Kumiai Chemical), ipfencarbazone (Hokko Chemical), and fenoxasulfone (Kumiai Chemical) have been in development since 2008. The fourth compound, dime-sulfazet, just obtained an ISO common name in early 2020.21)

Pyroxasulfone (Axeev®, Zidua®) is an herbicide for upland crops such as wheat, soybeans, and corn. It shows high efficacy

against hardly controllable gramineous weeds such as Johnson grass and Urochloa platyphylla and is also highly effective against weeds that have acquired resistance to glyphosate, ALS inhibi-tors, ACCase inhibitors, and dinitroaniline herbicides.87,101)

Ipfencarbazone (Winner®, Fighter®) is a triazolinone-based herbicide developed for paddy rice and exhibits high herbicid-al activity against Echinochloa spp. from pre-emergence to the three-leaf stage while being safe for transplanted rice at a dosage of 250 g a.i./ha.102,103) It has excellent effect persistence and has a

Table 9. PPO-inhibiting herbicides

a) Although there is no report that it is a PPO inhibitor, it is presumed to be a PPO inhibitor from the chemical structure.

Table 8. HPPD-inhibiting herbicides


residual effect for about 70 days against barnyard grass.Fenoxasulfone displays excellent herbicidal activity against

Echinochloa spp. and other annual weeds at 150–200 g a.i./ha with long residual activity.104) Fenoxasulfone was registered in Japan in 2014, and various products containing fenoxasulfone have been launched.

Dimesulfazet (Nissan Chemical), which belongs to trifluoro-methansulfonanilides, is presumed to be a VLCFAE inhibitor, since trifluoromethansulfonanilides such as mefluidide and per-fluidone have been reported to inhibit a very-long-chain fatty

acid synthesis.105)

7.3.5. Auxin-like herbicides and herbicide safenerAuxin-like herbicides include phenoxy carboxylic acids, benzoic acids, pyridine/pyrimidine carboxylic acids, and quinoline car-boxylic acids. In recent years, mainly pyridine/pyrimidine com-pounds have been subjected to development.87)

Table 11 shows information on two auxin-like herbicides, halauxifen-methyl and florpyrauxifen-benzyl. Halauxifen-methyl (Arylex™), developed by Dow (Corteva Agriscience), is a pyridine-type auxin-like herbicide and is highly effective on

Table 10. VLCFAE-inhibiting herbicides

Chemical structures Common name (Group name)Company name Registration year

Target crop RemarksDoseTarget weed

PyroxasulfoneKumiai Chemical2011

WheatSoybeanCorn

It shows broad herbicidal spectrum from gramineous weeds such as crabgrass, barnyard grass, and green bristle grass to broad-leaved weeds such as white goosefoot

IpfencarbazoneHokko Chemical2014

Paddy rice Dose： 250g/ha Barnyard grass, broad-leaved weeds

FenoxasulfoneKumiai Chemical2015

Paddy rice Dose：200g/ha Barnyard grass, broad-leaved weeds

Dimesulfazet a)（Sulfonanilides）Nissan ChemicalUnder development

Paddy rice

O NSO

O

NNF3C

OCHF2

N

NN

O

N

O

F

F

Cl

Cl

SO

OO N

Cl Cl

OEt

NHSOO

FF

F

N

O

a) Compound considered to be a VLCFAE inhibitor from its chemical structure

Table 11. Auxin-like herbicides and herbicide safener


major broadleaf weeds such as pigweed, henbit, corn poppy, flixweed, and chickweed at an extremely low dosage of 5–10 g/ha, with utility in multiple crops, the primary one being winter wheat.106) It is effective in managing weed biotypes resistant to other modes of actin such as ALS-inhibitor herbicides, glypho-sate, and triazine herbicides. It has been shown that the activity (sensitivity to horseweed) of halauxifen-methyl is different from that of 2,4-D and dicamba,107) which are typical auxin-like her-bicides.

Florpyrauxifen-benzyl (Rinskor™), developed by Corteva Agriscience, is also a pyridine-type auxin-like herbicide. It was unconditionally registered in the USA in 2017 and obtained ap-proval in the EU in 2019. It is highly effective at postemergence control of grasses, sedges, and broadleaf weeds in rice crops. It is also being evaluated for use in other crops, including corn. In a greenhouse experiment, florpyrauxifen-benzyl at 30 g a.i./ha provided ≧75% control of many weed species, such as broadleaf signalgrass, barnyardgrass, Amazon sprangletop, and large crab-grass.108)

As an herbicide safener, only one compound, metcamifen, can be mentioned. Metcamifen prevented an herbicide, clodinafop-propargyl, from damaging rice seedlings, and this was associ-ated with the enhanced detoxication of the herbicide.109)

7.3.6. Herbicide with a novel mode of actionAs already mentioned, since 2018, and for the first time in 30 years, three herbicides possessing new modes of action have ap-peared. Table 12 shows information on three herbicides possess-ing a novel mode of action. Cyclopyrimorate (Cyra®), developed by Mitsui Chemicals Agro and launched in 2019 in Japan, is a rice herbicide.89,110) It shows a broad herbicidal spectrum against Cyperaceae weeds and broadleaf weeds. It is also highly effective against weeds that have acquired resistance to ALS inhibitors. Further, it can be applied simultaneously to rice planting and direct sowing cultivation in paddy fields. The site of action of

cyclopyrimorate is HTS (homogentisate solanesyltransferase), a downstream enzyme of HPPD. In in vitro assays, HTS was inhibited strongly by DMC (a metabolite of cyclopyrimorate, des-morpholinocarbonyl cyclopyrimorate) and weakly by cy-clopyrimorate. Although it has already been reported that HST inhibitors have herbicidal activity, cyclopyrimorate is the first commercial herbicide having this mode of action.

Tetflupyrolimet is a novel herbicide class of aryl pyrrolidinone anilides under development by FMC, the ISO common name being given in January 2019. It interferes with de novo pyrimi-dine biosynthesis via the inhibition of dihydroorotate dehydro-genase (DHODH).90) It has demonstrated a high level of activity against grasses.

Cinmethylin is an herbicide whose registration has expired, at least in Japan. It has recently been revealed by BASF scientists that cinmethylin binds to fatty acid thioesterase (FTA), a new herbicidal site of action, and inhibits plant fatty acid biosynthe-sis.88) BASF has recently developed cinmethylin (Luximax, trade name: LuximoTM)) as an herbicide to control key grasses in cere-als. It demonstrates excellent efficacy against blackgrass and rye-grass, including resistant biotypes, while maintaining crop selec-tivity.111) Australia granted the world’s first approval to Luximo™ in 2019.112)

8. Concluding remarks

During the past decade, a wide variety of useful chemical pesti-cides that are safe to humans and environmentally friendly have been subjected to development. In the field of insecticides, acari-cides, nematicides, and fungicides, new chemicals that have or are likely to have a novel mode of action and unique chemical structure have been continuously developed. This is extremely important in avoiding the development of pesticide resistance and enabling sustainable agricultural production. It is of interest that in the herbicide field, for the first time in 30 years, herbi-

Table 12. Herbicide with a novel mode of action

Chemical Structures Common name Company name Registration year

Target crop RemarksDoseTarget weed

：

CyclopyrimorateMitsui Chemicals Agro2019

Paddy rice Dose：5～7.5g/ha Broad-leaved weedsand broad-leaved weeds.Highly effective against weeds thathave acquired resistance to ALS inhibitors

TetflupyrolimetFMCUnder development

Paddy rice Grass control

and

CinmethylinBASF2019

Existing herbicide found to have a novel mode of action


cides possessing a novel mode of action have appeared. This is significant for dealing with herbicide-tolerant weeds that have recently become a problem.

Though several new chemical pesticides originating from China (universities and companies) during the past decade are described in the present manuscript, this may not cover all new compounds from China. China’s dissemination of information (outside the country) on new pesticides seems insufficient, and some new compounds have been developed mainly for domestic use.

Chemical pesticides developed over the past decade have played an important role in crop protection and are expected to play an important role in the future. However, it is true that in recent years, the trend of global pesticide development has been gradually shifting from chemical pesticides to biological pesticides, GM crops, seeds, RNAi pesticides, and abiotic stress control agents. Of those, biopesticides are gaining popularity as lower-environmental-impact alternatives to conventional syn-thetic pesticides. The research and advisory firm Lux Research in Boston, MA, USA, has made an interesting and bold predic-tion concerning the relationship between chemical pesticides and biopesticides. As shown in Fig. 14, they predict that biopes-ticides will equal synthetic (chemical) pesticides in terms of market size by the late 2040s or early 2050s.113) It will be neces-sary to closely monitor the future trends of chemical pesticides.

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