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Pesticides in Japan

The Japanese industry started to develop in the late 19th century, By the 1960s, Japanese companies were already competent enough to develop their own new pesticides. MAS, the first domestically-produced fungicide, hit the markets in 1959, followed by MAF, an improved version, two years later and then MEP, an insecticide. Other major pesticides also emerged, such as cartap, an insecticide, blasticidin, an antibiotic, IBP, benthiocarb, a herbicide, and giberellin, a plant growth regulator.

By the 1970s, Japanese companies continued to develop new chemicals, resulting in the emergence of insecticides fenvalerate, buprofezin and hexythiazox, fungicides thiofanate-methyl, isoprothiolane and probenazole, and herbicides pyrazolate, sethoxydim and fluazifop-butyl.

By 21st century, Japanese companies were consolidating One of the key points of note of this time has been the emergence of ultra-high-performance pesticides.

One typical example is the insecticide imidacloprid, a ground-breaking chemical modelled on nicotine, a natural product. Japanese companies also invented a number of compounds similar to the sulfonylurea herbicide produced by Du Pont, which is effective with an ultra-low dosage of several grams to several tens of grams per hectare.

What is worthy of note here is that around half of the latest, high-performance pesticides used in Japan today were developed by Japanese companies. They are used as important and key pesticides not only in Japan, but overseas as well.

Pesticides before 1990

In 1967, Takeda Pharmaceutical invented and marketed Cartap (Padan), an insecticide with a unique chemical structure. Modeled on nereistoxin found in marine animals, this compound became widely popular as it was effective against a wide variety of pest insects. The outstanding academic research was also a good achievement for Japan.

Ihara Agrochemical developed and marketed MAS (Asozin), a fungicide for rice sheath blight and Japan’s first domestically-produced pesticide, in 1959, followed by MAF (Neoasozin).

Blasticidin S is the world’s first agricultural antibiotic, discovered by the University of Tokyo in 1961 and jointly developed by Kaken Chemical, Toa Agricultural

In 1965, Hokko Chemical developed Kasugamycin, an antibiotic for rice blast. These two products held much academic value.

In 1965, Ihara Agrochemical (now Kumiai Chemical) brought out EBP (Kitazin), followed by IBP (Kitazin P). Together with Blasticidin, these organophosphate rice blast treatments became wildly popular   as a non-mercurial secret weapon in the war against crop diseases.

Polyoxin is an agricultural antibiotic that is very effective against diseases such as rice sheath blight, powdery mildew on fruit and vegetable plants, Alternaria alternata in pears and Alternaria mali in apples. It was discovered in 1967 by RIKEN researchers and developed by Kaken Chemical. Other agricultural antibiotics include Validamycin (Validacin), effective against rice sheath blight, developed by Takeda Pharmaceutical registered as a pesticide in 1972.

Takeda Pharmaceutical also marketed Mildiomycin (Milanecin), very effective against powdery mildew, in 1983.

Herbicides and Plant Growth Regulators

While the herbicide PCP mentioned above was registered in 1956, it rapidly grew in popularity for rice cultivation after it was developed into granules in 1960. However, the early conception that it was toxic to fish proved to be true. When the Agricultural Chemicals Control Act was amended in 1963, PCP usage was regulated and the use of substitute formulations was encouraged.

Two major Japanese herbicides appeared during this time. One was CNP (MO), developed by Mitsui Chemicals and registered in 1965 the other was Benthiocarb (Saturn), developed by Kumiai Chemical and registered in 1969. Benthiocarb is effective on perennial weeds and has become one of the top herbicide products for rice cultivation, recognized as a superior herbicide formulation.

A number of other herbicides were registered during this time as well. Photosynthesis-inhibiting traizine herbicides on the market included CAT (Simazine), Prometryn (Gesagard), Atrazine (Gesaprim) and Simetryn (Gibon). Urea pesticides included DCMU (Carmex), Linuron (Lorox) and Siduron (Tupersan), while DCPA (Stam) was a typical amide pesticide. Dinitroaniline herbicide Trifluralin (Trefanocide) was used on a variety of crops including rice, wheat and vegetables and was particularly effective against rice weeds. Trifluralin is still widely used today.

Let us now mention plant growth regulators. Giberellin, developed by Kyowa Hakko, was officially registered on the pesticide register as a plant growth regulator in 1964. While it is mainly used on seedless grapes, it has a number of other applications as well. Giberellin is definitely worth a special mention, as the entire process

Hydoroxyisoxazole (Tachigaren), shown to be effective from its discovery in the early 20 century to the against soilborne diseases such as seedling wilt, brown determination of its structure and its development as a pesticide has been spearheaded by Japanese technology. Other products were developed and marketed during this time, including rooting promoter 1-Naphthyl-acetamide (Rootone), fruit accelerator 4-CPA (Tomato-tone) and growth retardant Daminozide (B-nine). These are still in use today.

Insecticides

While the main insecticides during this period were organophosphates, a number of new ones appeared that were comparatively low-toxic. However, many of these disappeared off the market with the appearance of high-performance pesticides. The following are typical examples of these pesticides still in use today.

Dow registered Chlorpyrifos (Dursban) in 1971. Sankyo developed and registered Isoxathion (Karphos) in 1972. Even today, this product is widely used because of its effectiveness against a wide range of pest insects on fruit and vegetable plants. Chevron developed Acephate (Orthene) and put it on the market in 1973. This product is highly systemic and can be used in the planting hole as well as sprayed; it still has a ¥7 billion market.

Bayer Japan developed Prothiofos (Tokuthion) in 1975. This pesticide is still widely used on fruit and vegetable plants because of its delayed but durable effects and its effectiveness against a wide range of insect pests, including soil pests.

ICI marketed Pirimiphos-methyl (Actellic) in 1976. Thus, a number of organophosphate insecticides were developed and although they are still used today, the competition to develop new ones all but came to an end during this period. The next insecticides to appear on the scene were the second generation carbamates in the 1980s; these were far less toxic to mammals. The first on the market was Carbosulfan (Advantage) in 1983. This was followed by Benfuracarb, registered by Otsuka Chemical in 1986. The next to appear was Alanycarb (Orion), developed by Otsuka Chemical in 1991.

With the advent of the 1980s, a number of new major insecticides appeared with completely different chemical structures from the existing products. In 1983, Sumitomo Chemical put Fenvalerate (Sumicidin) on the market – the world’s first pyrethroid for agricultural use.

In 1983, Nihon Nohyaku put out Buprofezin (Applaud). This was the first insect growth regulator (IGR) produced in Japan.

Nippon Soda registered Hexythiazox (Nissorun) in 1985, the forerunner of the high-performance miticides.

Fungicides

Several world-renowned Japanese fungicides were developed in the 1960s. Nippon Soda first brought out Thiophanate (Topsin) in 1969, followed by the more effective Thiophanate-methyl (Topsin M) in 1971.

These new fungicides had unprecedented chemical structures; they had systemic activity and were highly effective against a number of diseases in fruit and vegetable plants and other crops. This pesticide became popular in Japan and a renowned product throughout the world.

Fthalide (Rabcide) was invented by Kureha and registered in 1970 as a fungicide for rice blast Fthalide strongly inhibits hyphal penetration after appressorium formation in Pyricularia oryzae. Its mode of action is known to work by inhibiting Melanin Biosynthesis Inhibitors Reductase (MBI-R) in Pyricularia oryzae (5).

Soon after Fthalide appeared, overseas manufacturers developed two   rice blast fungicides with the same effect. One was Tricyclazole (Beam), marketed by Dow in 1981; the other was Pyroquilone (Coratop), marketed by Ciba-Geigy in 1985.

Rice Blast Fungicides (MBI-R Inhibitors)

Two more major rice blast fungicides appeared during this period, both invented by Japanese manufacturers. One is Isoprothiolane (Fuji-one), invented by Nihon Noyaku and registered in 1974; the other is Probenazole (Oryzemate), invented by Meiji Seika and also registered in 1974. These became major pesticides and very popular due to the fact that rice blast was of frequent occurrence, the fact that both products had systemic activity and the fact that they were highly effective both for submerged applications and seedling box treatment.

Herbicides:

CNP (MO), a herbicide for controlling barnyard grass in paddy rice fields, was developed and marketed by Mitsui Chemicals in 1965,

Benthiocarb (Saturn) was developed and marketed by Kumiai in 1969.

Stauffer brought out Molinate (Ordram) in 1971. The following year, Rhône-Poulenc registered and marketed Oxadiazon (Ronstar), while Monsanto did the same with Butachlor (Machete). The emergence of these barnyard grass killers enabled a so-called “sequential application” involving multiple applications of products: a combination of pretreatments during the early rice growth phase and foliar-soil treatments during the medium growth phase.

Other barnyard   grass killers were developed. Ciba-Geigy developed Pretilachlor (Solnet) in 1984, followed by Bayer Japan with Mefenacet (Hinochloa) in 1986. Mitsubishi Yuka started selling Dimepiperate (Yukamate) in the same year. Stauffer went to market with Esprocarb (Fujigrass) in 1988, while Tosoh started marketing Pyributicarb (Eigen) the following year.

Next, we shall discuss Cyperaceae herbicides and broadleaf (including perennials) herbicides used in conjunction with barnyard grass treatments. While hormone herbicides such as 2,4-PA (2,4-D) and MCPB and triazine herbicides such as Prometryn and Simetryn were used for this purpose, a number of more effective herbicides were developed.

In 1979, Mitsui Chemicals developed and marketed Naproanilide (Uribest), highly effective against perennial weed Sagittaria pygmae Miq. (Urikawa)

In 1974, Showa Denko (now SDS Biotech) registered Dymron (Shoron), highly effective against Cyperaceae weeds, particularly Scirpus juncoides. This product is still widely used today in combination formulations.

Sumitomo Chemical started selling Bromobutide (Sumiherb) in 1986. This is a N-benzyl-butanamide with intentionally bulky substituents in the amide structure and is effective at low doses against perennial weeds such as Scirpus juncoides, needle spikerush (Eleocharis   acicularis)   and   flatsedge   (Cyperus serotinus)

Mitsubishi Yuka developed the similarly-effective Clomeprop (Yukahope) and started marketing it in 1988

Let us now discuss Pyrazolate (Sanbird), a herbicide with a completely new chemical structure developed by Sankyo and registered in 1979. Pyrazolate immediately gained popularity due to its superior efficacy Pyrazolate was arguably one of the first one-shot herbicide formulations.

Pyrazoxyfen, marketed by Ishihara Sangyo in 1985, and Benzofenap, developed by Mitsubishi Yuka in 1987. Other herbicides with the same mode of action but completely different chemical structures include isoxazole and triketone compounds, which have been actively developed since 1995. Thus, Pyrazolate sparked the development of a new division of paddy rice herbicides.

A super-herbicide for paddy-field broadleaf weeds appeared in 1987: Bensulfuron methyl, developed by DuPont. This super-herbicide brought the amount of active ingredient per hectare down into the double digits: 50-75g, far less than the existing products. The sulfonylurea (SU) chemical structure was completely unprecedented; it came to be called SU (ALS inhibitor) as its mode of action worked in a new way by inhibiting acetolactate synthase (ALS). SU first appeared in 1982 in the United States in the form of Chlorsulfuron for broadleaf weeds in wheat; Bensulfuron methyl was a modified version of this developed for use on paddy-rice fields. As this type of herbicide became known, many companies set out on research and development in the footsteps of DuPont. This resulted in the development and marketing of Pyrazosulfuron by Nissan Chemical in 1989, Imazosulfuron by Takeda Pharmaceutical in 1990 and Halosulfuron by Nissan Chemical in 1993. The ensuing competition to develop SU herbicides has continued to this day.

Meiji Seika developed and registered the non-selective herbicide Bialaphos (Herbiace) in 1984. This product is a metabolite produced by Streptomyces hygroscopicus bacteria and was the first herbicide in the world produced by fermentation.

Nippon Soda developed and registered grass-weed herbicide Alloxydim (Kusagard) in 1980, followed by Sethoxydim (Nabu) in 1985. With a completely unprecedented cyclohexanedione chemical structure, these were major world-renowned products developed for the sugar-beet, rapeseed, cotton and soybean markets. Significant modifications were later added to this chemical skeleton to develop several related herbicides.

Ishihara   Sangyo    developed   and   registered Fluazifop-butyl (Onecide) in 1986. This product had the same effect as Sethoxydim, mentioned above; that is, it is selective against grass weeds. In 1989, Nissan Chemical developed and marketed Quizalofop-ethyl (Targa), which has a similar chemical structure. Since the main market for these two formulations is overseas, they were promoted with overseas development in mind from the beginning.

Insecticides

A number of highly effective insecticides have been developed since 1990, leading a transition from the age of organophosphates and carbamates to an era of new insecticides with new modes of action. Of the 61 newly registered active ingredients     for insecticides (excluding pesticides with lapsed registrations and biopesticides such as natural enemies) registered by 2011, 34 (55.7%) were invented by Japanese companies. This is a good example of the strong research and development capabilities of Japanese companies. Let us now outline some of the main Japan-made insecticides.

There are three organophosphate formulas developed for use against soil pests. Ishihara Sangyo registered Fosthiazate (Nematorin) in 1992 Cadusafos (Rugby) in 2001, while Agro-Kanesho registered Imicyafos (Nemakick) in 2010

Shinzo Kagabu, of Nihon Tokushu Noyaku (now Bayer Japan), invented Imidacloprid (Admire) and registered it in 1992. Called a neonicotinoid, as its mode of action is similar to the natural insecticide nicotine, it became the best-selling insecticide in the world, reaching ¥100   billion in sales. It truly is a super-pesticide. This insecticide sparked intensive research and development by various companies over the next decade, resulting in another seven neonicotinoids by 2002, each with different characteristics.

There was a flurry of research on insect growth regulators (IGRs) – named for their insecticidal effect caused by a new mode of action – during this time, with a significant number of IGRs produced. Buprofezin (Applaud), with a thiadiazine structure, was the first IGR to be produced in Japan, brought out by Nihon Nohyaku in 1983.

Duphar brought out the benzoylphenylurea (BPU) compound Diflubenzuron (Dimilin) in 1981. This caught the attention of other companies, who then worked on BPUs, resulting in another seven products by the present day.

During this period, companies also developed IGRs modeled on the insect hormone ecdysone (a steroidal prohormone that governs ecdysis and metamorphosis, also called molting hormone or prothoracic gland hormone).

These have a dibenzoyl hydrazine structure and are very effective against Lepidoptera larvae on fruit and vegetable plants. They have the advantage of being highly selective and so have little effect on natural enemies and pollinators.

The first of these was Tebufenozide (Romudan), registered and marketed by Rohm and Hass in 1994. This was followed by Chromafenozide (Matric) in 1999, jointly developed by Nippon Kayaku and Sankyo. In 2001, Rohm and Hass developed and marketed Methoxyfenozide (Falcon) (15). These products work as insecticides by disrupting feeding behavior and promoting ecdysis within a few hours of being eaten by insects.

Sumitomo Chemical developed and marketed Pyriproxyfen (Lano) in 1995. This IGR works as an insecticide by promoting larva growth and preventing metamorphosis in the same manner as a juvenile hormone (JH).

Similarly-acting insecticides include Methoprene, used for disease control against flies and mosquitoes, and Fenoxycarb (Insegar), registered by Maag in 1990 as an insecticide for Lepidopterae (registration lapsed in 2004).

Pyriproxyfen is quite stable in light and is very effective against hard-to-kill insects such as whiteflies, thrips and scale insects. It has a number of different effects on insects at the juvenile stages, such as inhibiting metamorphosis in larvae, inhibiting adult eclosion and preventing eggs from hatching, but it has no effect on adult insects

Let us now discuss the miticides that emerged during this period, which were unprecedented both in terms of chemical structure and mode of action. Fifteen of these miticides have now been registered since the appearance of Hexythiazox (Nissorun) in 1985, mentioned previously. Five of these are inventions by overseas manufacturers, while the remaining ten were all invented and developed by Japanese manufacturers. Miticides have a relatively small global market as well as quite a short product lifespan. Accordingly, it is quite difficult to recoup any research and development costs and, as a result, major overseas corporations have tended to put less effort into developing miticides than Japanese companies have.

Milbemectin (Milbenock, Koromite) is a miticidal antibiotic produced by actinomycetes found in the soil in Hokkaido and isolated by Sankyo. This was developed into a mixture of Milbemycin A3 and A4 and put on the market in 1990. Highly effective against a broad range of mites, it is widely used on fruit and vegetable plants as there has been no observed cross-resistance as seen in existing miticides. Its mode of action is achieved by functioning as an agonist

While Lepimectin (Aniki) is not a miticide, we shall mention it here as it has a similar chemical composition to Milbemectin. Registered as a pesticide in 2010 by Sankyo (now Mitsui Chemicals Agro), it was discovered by altering the structure of Milbemectin (ester structure added at the 13-position) to give it an insecticidal effect. It works rapidly on insects such as Lepidopterae, Hemipterae and thrips and is particularly effective against butterflies

Our discussion now turns to the miticides from this period in the mitochondrial electron transport inhibitor (METI) category. Nissan Chemical developed and marketed Pyridaben (Sanmite) in 1991, while Nihon Nohyaku did the same for Fenpyroximate (Danitron) the same year This was followed by the development and sale of Tebufenpyrad (Pyranica) by Mitsubishi Chemical in 1993 and Pyrimidifen (Miteclean) by Ube Industries/Sankyo in 1995 . These high-performance miticides started to dominate the industry from the late 1980s onwards, when the afore-mentioned Hexythiazox was in its heyday. These formulations rapidly gained popularity in the early 1990s, accounting for half of the miticide market. They were all effective at low doses, fast-acting and worked at all stages in the spider-mite life cycle.

Another compound with the same mode of action is Tolfenpyrad (Hachihachi), developed as an insecticide. This product was jointly developed by Mitsubishi Chemical and Otsuka Chemical and registered in 2002. It is widely popular due to its superior effectiveness against a wide range of insects, including Lepidopterae, Hemipterae and thrips. It is also effective against powdery mildew on eggplants, watermelons and other plants.

Etoxazole (Baroque) is a new miticide invented by Yashima Chemical and registered in 1998. Yashima Chemical came up with Etoxazole through research on oxazoline chemistry. While it is not very effective on mature spider-mites, it is incredibly effective against insect eggs and nymphs. In terms of its ppb level, it is 100 times more powerful than other miticides such as Hexythiazox. Its mode of action is not yet clearly known, although it is presumed to work like Hexythiazox by inhibiting ecdysis .

Otsuka Chemical invented Cyflumetofen (Danisaraba), a miticide with a completely new benzoylacetonitrile structure and put it on the market in 2007. It is fast-acting and is specific to spider-mites while having no effect on beneficial insects. Its mode of action is conjectured to work by inhibiting Complex II in the mitochondrial electron transport chain.

Nissan Chemical invented acrylonitrile miticide Cyenopyrafen (Starmite) and registered it in 2008. Cyenopyrafen has strong ovicidal activity for all kinds of spider-mites and has none of the cross-resistance issues seen in existing miticides. Like Cyflumetofen, mentioned above, it works by inhibiting Complex II in the mitochondrial electron transport chain .

Nihon Nohyaku presented a report on the powerful miticide Pyflubumide (NNI-0711) at a conference in 2012 It also works by inhibiting Complex II in the mitochondrial electron transport chain, although it is still in development and has not yet been put on the market.

Thus, previously unimaginably highly effective miticides were successively developed. overseas manufacturers developed other miticides during     this   time,   these   have   all   been domestically-developed products pioneered by Japanese manufacturers (such as Acequinocyl, Bifenazate and Fluacrypyrim).

Insecticide :

Sumitomo Chemical invented Pyridalyl (Pleo) and put it to market in 2004. Highly effective against Lepidopterae and thrips, it is also effective against pest insects that have become resistant to existing pesticides, such as organophosphates, synthetic pyrethroids and IGRs. While its mode of action is not yet clearly known, it is thought to work through a completely unprecedented mechanism

Ishihara Sangyo developed a fluorine-containing pyridine insecticide, Flonicamid (Ulala), and registered it in 2006. While it has no effect on Lepidopterae, it is selectively effective against aphids and thrips on fruit and vegetable plants and has systemic activity. Its mode of action is unknown, but it does not fit into any of the existing categories .

In 2007, Nihon Nohyaku developed and marketed Flubendiamide (Phoenix), with an unprecedented phthalic acid diamide structure and a completely new effect. It causes the body of the insect to fatally crumple up on itself. Its mode of action is achieved by acting on the ryanodine receptors (RyRs) that govern the contractions of the insect’s muscles. Flubendiamide activates the RyRs, releasing calcium ions into the muscles of the insect and causing the insect to fatally crumple up.

DuPont   won   out with the development of Chlorantraniliprole (Acelepryn), which has similar effects, registering it in 2009. A number of manufacturers are currently focusing on this area of pesticides and future developments are promising.

Nihon Nohyaku developed Metaflumizone (Accel), an insecticide with a semicarbazone structure, and registered it in 2009. It is very effective against Lepidopterae on vegetable and tea plants. Reports show that its mode of action works in the sodium channel in the nervous system. While synthetic pyrethroids are known to work in the sodium channel, Metaflumizone is thought to have a different mode of action, as it also works on insects that have built up a resistance to synthetic pyrethroids.

Nihon Nohyaku registered quinazolinone-structured Pyrifluquinazon (Colt) in 2010. This formulation is highly effective against aphids, stink bugs, thrips and scale insects on fruit and vegetable plants. It is categorized as an insect behavior regulator (IBR), as it prevents insects from feeding and sucking and causes them to immediately drop off plants . While its mode of action is not clearly known, it is similar to Pymetrozine (Novartis), which went on the market in 1998.

Nihon Nohyaku started investigating methoxyacrylate fungicides in the late 1980s. They discovered that the aminoquinazoline derivative they had synthesized as an intermediate had insecticidal properties, so they researched it further. They introduced the perfluoroalkylated aniline structure, the intermediate in Flubendiamide, resulting in Pyrifluquinazon.

A number of pesticides that have emerged during this period are highly effective, safe to mammals and have little impact on the environment. A succession of new products is being developed with unprecedented chemical structures, new pesticidal characteristics and new modes of action. Although there are high hurdles to surmount in development, it is worth noting that many of the new products have been discovered by Japanese companies and many of these have become world-renowned products. As insects have begun to build up resistance to existing insecticides, there is a continuous need for new insecticides with new modes of action and further development is expected.

Fungicides

First, let us mention the rice blast fungicides that work by inhibiting biosynthesis of melanin. Kureha developed and marketed Fthalide (Rabcide) in 1970. this is classified as a MBI-R, a second-generation MBI. Other MBI formulations with new chemical structures different from Fthalide were developed in the late 1990s. As shall be mentioned later, these formulations are third-generation MBIs, called MBI-Ds, because they act at a different step in the rice blast melanin biosynthesis process from Fthalide, inhibiting the scytalone dehydrogenase.

Bayer Japan developed and marketed Carpropamid (Win) in 1997. Inventor Shinzo Kagabu had been focusing on substituted cyclopropane-carboxylic acid derivatives and examining related compounds after reading a published paper on momilactone as an inducer (resistance inducer) of rice phytoalexin

Sumitomo Chemical developed and marketed Diclocymet (Delaus) in 2000, while ACC and Nihon Nohyaku did the same for Fenoxanil (Achieve) the same year.

Takeda Pharmaceutical developed and marketed Ferimzone (Take-blass) in 1991. Reports indicate that, unlike the MBIs, this fungicide acts on the cellular membrane to prevent hyphal growth

Diclocymet (Delaus)       Fenoxanil (Achieve)       Ferimzone (Takeblass)

The first EBI developed in Japan was Triforine (Saprol), invented by Celamerck and registered in 1977. In 1983, Bayer marketed Triadimefon (Bayleton). This triggered other companies to start their own development and a number of other EBIs emerged. The EBI development rush lasted 20 years from the late 1980s. There are more than 20 EBIs currently registered in Japan. Seven of these are Japanese inventions, each with their own distinguishing characteristics.

Just as the development competition over EBIs ebbed a little into the 1990s, a new fungicide emerged with a new mode of action: strobilurin fungicides, modeled on natural strobilurin, a fungicidal substance found in Strobilurus tenacellus, a type of basidiomycete . This has a distinctive methoxyacrylate structure. The first strobilurin   fungicide   registered   in   Japan   was Kresoxim-Methyl (Stroby), developed by BASF and registered in 1997. This was followed by Azoxystrobin (Amistar), developed by Zeneca and registered in 1998. Later, more than 20 companies competed to develop the next strobilurins, ushering in the age of the strobilurin fungicide. Currently, there are 10 such products on the pesticide register. Two of these were developed by Japanese companies

 

Shionogi invented Metominostrobin (Oribright) and put it to market in 1998. This product proved to be effective against rice blast and a wide range of other rice diseases such as sheath blight and leaf blight. While the research team at Shionogi was developing isoxazole derivatives as herbicides, they also noted that these had some minor fungicidal effects. They developed this into a ring opened   heterocyclic   structure,   resulting in Metominostrobin.

Kumiai Chemical registered Pyribencarb (Fantasista) very recently, in 2012. This formulation is distinctive for its suitability for a wide range of diseases on fruit and vegetable plants as well as its effectiveness against fungi that have grown resistant to strobiluri. It has only just been registered, but it is expected to grow in popularity in future.

The mode of action of the strobilurins mentioned above is known to work by inhibiting respiration in fungi by inhibiting Complex III (Qo) in the mitochondrial electron transport chain. This effect is achieved by strobilurins, mentioned above as being produced by molds; however, this does not mean that strobilurins inhibit respiration in molds. Reports indicate that these fungi have various defense mechanisms in place, such as low susceptibility at the point of action. The growing resistance to these types of fungicides in powdery mildew in wheat and downy mildew in cucumbers could have something to do with these defense mechanisms.

Japanese companies have invented a number of other fungicides besides EBIs and strobilurins since 2000. Each of these has a different mode of action from the two mentioned above and is effective against fungi that are resistant to existing formulations.

Ishihara Sangyo registered Cyazofamid (Ranman) in 2001 and put it on the market. It is effective against late blight in potatoes and downy mildew in grapes (both oomycetes). Initially sold in Japan, it later spread throughout 16 countries. It was discovered as a result of further developments on cyanoimidazole and benzimidazole structures, known through patents to have fungicidal properties. While its mode of action is achieved by inhibiting respiration, like the strobilurins, it is known to act in a different position (electron transport chain Complex III (Qi)

Nippon     Soda      developed     and     registered oxime-ether-structured Cyflufenamid (Pancho) in 2002. This fungicide is distinctive for its broad ranging effects on powdery mildew on wheat, vegetables and fruit plants, as well as its effectiveness against diseases showing signs of resistance to existing fungicides. Nippon Soda already had experience with oxime-ether compounds from having developed the herbicide Alloxydim and presumably applied this knowledge to existing fungicides to produce Cyflufenamid. While its mode of action is completely different from any existing formulations, the details of it are not yet clearly known

 

Kumiai Chemical developed and marketed Benthiavalicarb isopropyl (Mamolot) in 2007. This fungicide has an amino acid valine amide carbamate structure and works as both prevention against and cure for blight and downy mildew. Kumiai worked on developing structures based on the fungicidal properties of valine derivatives patented by Bayer, resulting in this benzothiazole skeletal structure. Reports indicate that its mode of action is achieved by inhibiting biosynthesis of cell walls

Nissan Chemical developed sulfamoyltriazole-structured Amisulbrom (Leimay) and put it to market in 2008. This product is highly effective against blight and downy mildew, penetrating quickly into plants to produce a high preventive effect While its mode of action is presumed to work by inhibiting respiration like the aforementioned Cyazofamid, no detailed reports have been made. The two are similar in chemical structure, both having a sulfamoyl-based azole skeleton.

Mitsui Chemicals developed and marketed carboxylic acid-amide-structured Penthiopyrad (Affet) in 2008. This product shows superior effectiveness against a wide range of diseases, such as grey mold, powdery mildew, leaf mold, scab and monilia blossom blight. It is also highly effective against fungi that have developed resistance to existing fungicides. Its mode of action works by inhibiting succinate dehydrogenase in the respiratory electron transport chain Complex II While other carboxylic acid-amide fungicides have been developed with this mode of action, such as Mepronil (Basitac; registered by Kumiai Chemical in 1981), Flutolanil (Moncut; registered by Nippon Soda in 1985) and Furametpyr (Limber; registered by Sumitomo Chemical in 1996), Penthiopyrad is highly effective against diseases that these other fungicides have failed to beat. It is also effective against newly problematic diseases that have developed resistance to EBIs and strobilurins.

Ishihara Sangyo started marketing Pyriofenone (Property) in the United Kingdom. This fungicide has a benzoylpyridine structure and is very effective against powdery mildew in wheat, cucumbers and other crops

The fungicidal action of this fungicide is achieved by inhibiting the formation of haustoria and conidia in the parasitic fungus and interfering with the morphology of secondary appressoria and hyphae. The chemical structure of this product was developed by replacing the benzene ring in Metrafenone, developed by BASF, with a pyridine ring – the result of Ishihara’s wealth of experience with pyridine. This product has not yet been registered in Japan.

Herbicides

Let us examine the developments in herbicides from the 1990s onwards. Besides the paddy rice barnyard grass killers, a number of other effective herbicides appeared during this time.

Researchers in the late 1990s worked on modes of action and clarified that chloroacetamide herbicides (such as Butachlor and Pretilachlor), which had previously been thought to work by inhibiting protein synthesis,     actually     worked     by     inhibiting Very-Long-Chain Fatty Acid Elongase (VLCFAE) in fatty acid synthesis This prompted the development of a number of herbicides having this mode of action.

Tokuyama Soda (now Tokuyama) started pesticide research and development in 1980, working jointly with Utsunomiya University. A study involving adding various heterocycles to chloroacetamide herbicides resulted in Thenylchlor (Alherb) with a thiophene heterocycle, registered in 1993. Multiple times more active than existing chloroacetamide herbicides, it was very effective not only against barnyard grass, but also against Cyperaceae and Monochoria vaginalis.

Hodogaya Chemical developed and marketed Etobenzanide (Kickby) in 1995. Selectively effective against barnyard grass, this was used in combination formulations

Chugai Pharmaceutical invented Cafenstrole (Himeadow) and put it on the market in 1996. Effective against barnyard grass until the 2.5 leaf stage and long-lasting, it is very popular as a base substance for combination formulations. By 1998, it was a major herbicide.It is also suitable for use on turf. Its carbamoyl triazole structure is unprecedented among herbicides

Indanofan (Trebiace) is a new herbicide combining an oxirane ring with an indandione structure. Inspired by the oxirane-structured maize herbicide Tridiphane (no longer in use), Mitsubishi Chemical worked on developing its own compound, resulting in Indanofan, with a new chemical structure previously unseen in a herbicide, and registered it in 1999. This product is very effective against barnyard grass at the 2.5 leaf stage and broad-leaf weeds at a low dosage of 120-150g per hectare

Fentrazamide (Innova) is a paddy rice herbicide invented by Bayer Japan. Registered in 2000, this product became very popular, marketed as the main ingredient in a combination formulation, making a name for itself as a key barnyard grass killer. While Uniroyal was the first to identify the herbicidal properties of the tetrazolinone structure, the herbicidal effect on barnyard grass significantly increased with improvements to the structure

Kumiai Chemical developed Fenoxasulfone, very effective against barnyard grass and also annual weeds, and applied for registration in 2012. It is expected to become   a   popular     formulation.   With   a sulfonyl-substituted isoxazoline structure, it should be very effective at low doses of 100-250g. Kumiai Chemical also developed the similarly-structured Pyroxasulfone, which is very safe on major crops such as wheat, maize and soybeans, very effective against broadleaf weeds such as Chenopodium album (Common lambsquarters) and Abutilon theophrasti (velvetleaf) and also effective on glyphosate-resistant weeds, which have become a problem in recent times. Pyroxasulfone was registered in 2011 in Australia and in the United States

All of the herbicides discussed here work by inhibiting VLCFAE, mentioned above. While these represent a wide range of different chemical structures, there is still potential for a completely new compound to be discovered that works in the same way, and there is much promise for future development. This is a good example showing the importance of researching the target mode of action when inventing new pesticides.

Next, we shall discuss carotenoid synthesis (4-HPPD) inhibitors, which have been actively researched since the late 1990s. the forerunner of these formulations was Pyrazolate (Sanbird), developed by Sankyo in 1979. Once Japanese       companies       started       developing pyrazole-structured herbicides in the late 1980s, no further development was done on pyrazole derivatives. SDS Biotech later discovered the triketone derivative Benzobicyclon (Show Ace) and registered it in 2001. While it had been known since the 1980s that triketone-structured compounds had herbicidal effects, SDS started developing it for use on paddy rice fields. After a number of modifications to the structure,

Benzobicyclon became the first such herbicide highly suited for use in paddy rice cultivation. It proved to be very effective against annual broadleaf weeds and perennial weeds at doses of 200-300g per hectare It rapidly became popular due to its effectiveness on weeds such as Scirpus juncoides and Monochoria vaginalis that had become resistant to SU herbicides; Other herbicides in this category include Tefuryltrione (Mighty One), developed and marketed by Bayer Japan in 2010, and Mesotrione (Callisto), developed and marketed by Syngenta.

Much research has gone into the area of 4-HPPD inhibitors since the appearance of the triketone structure and future developments are expected.

Finally, let us discuss the significant development that has taken place during this period on herbicides that work by inhibiting chlorophyll biosynthesis. Compounds with this effect have a long history dating back to diphenyl ether herbicides. let us mention here that NIP (registered in 1963), CNP (registered in 1965) and Chlomethoxynil (X-52) require light in order to work as herbicides and were thus initially called light dependent or photobleaching herbicides. Later, Rhône-Poulenc developed Oxadiazon (Ronstar), with a completely different chemical structure. This formulation is still used as a paddy rice herbicide. Mitsubishi   Chemical    developed   and   marketed cyclic-imide-structured Chlorphthalim in 1981. This formulation is still used today as a herbicide for turf. While these products have completely different chemical structures, they are light-dependent herbicides, like the diphenyl ether products.

Sumitomo Chemical developed Flumiclorac pentyl (Resource) in 1994 as a herbicide for use on soybeans and also registered Flumioxazin (Sumisoya) in Japan in 2000. It then registered this product in the United States in 2001 for use on soybeans and peanuts

Kaken Pharmaceutical developed Pentoxazone (Vexor) for use on barnyard grass and broadleaf weeds and put it to market in 1997. Effective against annual weeds in general, this product is also very effective on common false pimpernel and Monochoria korsakowii (mizuaoi) that have become resistant to sulfonylurea pesticides Currently, more than 40 combination formulations include this product and it is very popular as a paddy rice herbicide.

Nihon Nohyaku developed and marketed Pyraflufen ethyl (Ecopart) in 1999. This formulation is highly effective on broadleaf weeds (such as Galium spurium) in wheat at low doses comparable with sulfonylurea pesticides (6-12g/hectare). It has also been registered overseas in Europe. Unlike the existing PPO inhibitors, this formulation has a unique chemical structure, with a benzene ring bonded to hetero ring carbon atoms (C-C bond)

Kumiai Chemical developed and marketed Fluthiacet methyl (Velvecut) in 2002. This product is very effective on Abutilon theophrasti (velvetleaf), a noxious weed on maize crops, at doses of 3-10g/hectare It was registered in the United States in 1991 for use on soybeans and maize.

Disclaimer : Above information is compiled from open source publication and Author donot claim their accuracy. It is intended to develop Indian Agriculture and Students of Agribusiness