AgriChem 1
AgriChem 1
AgriChem 1
Received: 7 September 2015 Revised: 27 October 2015 Accepted article published: 18 November 2015 Published online in Wiley Online Library: 29 December 2015
Abstract
Agriculture is facing an enormous challenge: it must ensure that enough high-quality food is available to meet the needs of
a continually growing population. Current and future agronomic production of food, feed, fuel and fibre requires innovative
solutions for existing and future challenges, such as climate change, resistance to pests, increased regulatory demands,
renewable raw materials or requirements resulting from food chain partnerships. Modern agricultural chemistry has to support
farmers to manage these tasks. Today, the so-called ‘side effects’ of agrochemicals regarding yield and quality are gaining
more importance. Agrochemical companies with a strong research and development focus will have the opportunity to shape
the future of agriculture by delivering innovative integrated solutions. This review gives a comprehensive overview of the
innovative products launched over the past 10 years and describes the progress of modern agricultural chemistry and its future
prospects.
© 2015 Society of Chemical Industry
1 INTRODUCTION pests and disease, a higher risk of crop failure and increasing crop
The modern agrochemical industry is currently confronted with and food prices.8 While there are opportunities for making use
elemental tasks and many challenges.1 These challenges include of regions that are not available for agriculture today, the overall
consumer preferences, which are focusing more and more on qual- reliability of agricultural output is threatened.
ity, including ethical aspects and a healthier diet, high demand for Within the coming years, enormous challenges will be presented
the raw materials, tougher corporate competition, stringent regu- by further energy demand and the increasing world population,
lations and the need for continual innovation. with increased food, feed and water consumption, as well as global
In order to guarantee the food, feed, fibre and fuel production warming. Currently, an intensive search for the right answers is
in high yield and quality, the best economical, ecological and under way, involving politics and cooperation between nations
environmental practices for sustainable agriculture are essential.2,3 and the public and private sectors, as well as science, research and
For example, for several years scientific and technological technology.
advances have been opening up new possibilities for farmers But what will be the role of the modern agricultural chemistry in
the future ?
in the global world. The networked digital farm of the future
is already making agriculture more efficient and sustainable
today (http://www.cropscience.bayer.com/en/Magazine/Digital-
Farming.aspx). 2 NEED FOR INNOVATION
Promising results of current high-throughput field phenotyping Continual innovation in modern agricultural chemistry is vital, as
methods can be used as a basis for developing and improving reflected in the field of crop protection and stress relief. Based on
techniques to achieve reliable time- and cost-efficient pheno- analyses of major agricultural crops such as rice, wheat, barley,
typing platforms useful for precision agriculture, and to assist corn, etc., yields without crop protection would be reduced by
breeding programmes by monitoring important known traits or around 50% of those currently attained with crop protection
identifying novel traits.4 to control pests, weeds and diseases. However, given the losses
On the other hand, there is the strong impact of the biological due to pests, weeds and agricultural pathogens, as well as to
system (soil, plant, climate or habitat), combined with current storage and logistics failure, the theoretically attainable yield
challenges such as climate change,5 biotic or abiotic stress, soil could be around 170% of current yields. This means that, through
erosion, the growing world population, energy and workforce. innovations in the field of crop protection and stress relief (e.g.
In addition, with limited arable land and a continually growing
world population, the available farmland per capita is expected to
decrease dramatically, e.g. from 0.25 ha in 2000 to 0.16 ha in 2050.6 ∗ Correspondence to: Peter Jeschke, Bayer CropScience AG, Small Molecules
Climate change is ongoing and presents the risk of weather Research, Pest Control Chemistry, Building 6550, Alfred-Nobel Str. 50, D-40789
Monheim am Rhein, Germany. E-mail: peter.jeschke@bayer.com
extremes such as drought, flooding, storms and erosion, which can
result in desertification and a lack of water.7 Consequences could Bayer CropScience AG, Small Molecules Research, Pest Control Chemistry, Mon-
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be changes in local cropping patterns and in the prevalence of heim am Rhein, Germany
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www.soci.org P Jeschke
without abiotic stress),9 the total yield and quantity could be This article will describe a selection of the innovative agricul-
further increased significantly. tural chemicals launched between 2004 and 2014 as fungicides,
herbicides and safeners, insecticides and nematicides, focusing
2.1 Crosslinked biological system research on the most relevant biochemical targets or MoAs, with spe-
cial reference to products from Bayer CropScience (see Table 1).
An important aspect is (a) classical macroscopic undertand-
These are:
ing versus (b) enhanced microscopic understanding, including
interdependences of the crosslinked biological system, which is 1. Sterol biosynthesis (sterol-C14 -demethylase) (DMIs), respi-
mandatory to create the future of modern agriculture (Fig. 1). ratory chain succinate dehydrogenase inhibitors (SDHIs) of
In this context, the understanding of the correlation between complex II and so-called quinone outside (Qo -site) inhibitors
(a) water supply, soil quality, agrochemicals, biologicals and biotic of complex III, spectrin-like protein for fungicides and host
stress versus (b) agricultural crops and climate, symbionts, nutri- plant defence induction and cellulose synthase (cell wall
ents, habitat and abiotic stresses is important. biosynthesis).
2. 4-Hydroxyphenylpyruvate dioxygenase (4-HPPD), acetolactate
2.2 Market demands and innovative active ingredients synthase (ALS), protoporphorinogen-IX-oxidase (PPO), acetyl
For new active ingredients, the market demands are rapidly coenzyme A (CoA) carboxylase (ACCase) and cellulose biosyn-
changing because of emerging resistance in insects, weeds thesis (CBIs) inhibitors for herbicides as well as safeners for
and agricultural pathogens, as well as resistance management, 4-HPPD and ALS inhibitor herbicides and transport inhibitor
increased regulatory demands, requirements resulting from response 1 (TIR1)/auxin signaling F-box (AFB) proteins (auxin
food chain partnerships, invasive species of insects, weeds and herbicides).
agricultural pathogens and shifts in existing pests. 3. Nicotinic acetylcholine receptor (nAChR) competitive and
Therefore, there is a strong need for innovative active ingredients allosteric modulators, ryanodin receptor (RyR) modulators and
with favourable properties such as novel modes of action (MoAs), acetyl CoA carboxylase (ACCase) for insecticides.
for crop enhancement effects that could be used to improve plant 4. Acetylcholinesterase (AChE), osmotic signal transduction
health, for physicochemical properties such as systemicity that (MAP/histidine kinases) and respiratory chain succinate dehy-
could be used for seed treatment applications or for the highly drogenase (SDH) inhibitors for nematicides.
efficient drip irrigation method and for competitive economics.
Today, the agrochemical companies aim to supply integrated
solutions to the market, but major research and development 4 FUNGICIDES FOR DISEASE CONTROL
activities are still focused on innovation in agricultural chemistry. For many years, the basic cellular functions have been important
To illustrate the progress of modern agricultural chemistry and targets in fungicide discovery research. Only six MoAs dominate
the associated pros and cons, this article highlights selected around 80% of this market segment. These MoAs versus agricul-
agrochemicals that have been launched on the global crop pro- tural market products include around 30% DMIs such as triazole
tection market in the past 10 years, together with their target fungicides, 21% multisite/chemical reactives such as dithiocarba-
pests, pathogens or weed organisms defined by current farming mates, 19% Qo -site inhibitors of complex III such as strobilurin
practices. derivatives and 6% SDHIs of complex II. All the other MoAs are
much less important.
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Figure 1. Global trends and resulting current challenges: the agro-industry is confronted with elemental tasks (Klausener A, 12th IUPAC International
Congress of Pesticide Chemistry, Melbourne, Australia, 2010).
enantiomers, from which the (S)-(−)-enantiomer demonstrates their biological profile and application rates in different crops
higher activity than the racemate.14 Based on its broad fungici- (Table 2).21,22
dal spectrum, excellent bioavailability and long-lasting efficacy, The structures of the fluorinated SDHI fungicides can be
prothioconazole represents a systemic fungicide with protective explained in more detail. Whereas in penflufen the 5-position (R1 )
and curative properties. It has been developed to deliver a very is fluorine substituted, the other pyrazol-4-yl-carboxamide struc-
high standard for control of agricultural pathogens in cereals and tures are unsubstituted (R1 = H). The 3-position (R2 ) is alkylated
other arable crops.15,16 Prothioconazole provides excellent control (e.g. penflufen; R2 = CH3 ), but in most cases substituted with diflu-
of all relevant cereal pathogens, including stem base and ear oromethyl (R2 = CHF2 ) or trifluoromethyl (R2 = CF3 ) residues. As
diseases and all important leaf spot diseases, as well as cereal rust has been demonstrated for boscalid, the substituent R3 has to be a
(Puccinia spp.), powdery mildew (Blumeria graminis) and white halogen-substituted bisphenyl moiety (cf. bixafen, fluoxapyroxad)
mould (Sclerotinia sclerotorium) in oilseed rape and canola.17,18 or the second phenyl ring is replaced by a [1,1′ -bicyclopyropyl]-2-yl
Furthermore, it was shown that this novel DMI fungicide demon- (cf. sedaxane) or branched 1,3-dimethylbutyl side chain (cf.
strates plant-growth (PGR)-stimulating behaviour and represents penthiopyrad, penflufen). In penthiopyrad, the phenyl is replaced
a useful tool for resistance management.19 by a bioisosteric thiophene ring. Isopyrazam and the benzovindi-
flupyr are two members of the benzonorbornene amide subclass,
containing a bulky 1-methylethyl [CH(CH3 )2 ] or dichloromethylene
4.2 Respiratory chain succinate dehydrogenase inhibitors (=CCl2 )-substituted 1,2,3,4-tetrahydro-1,4-methano-naphthalene
(SDHIs) moiety in the 9-position.
During the past 10 years, halogen-substituted pyrazole- Both isopyrazam and bixafen demonstrate excellent activity
4-carboxamide SDHIs (FRAC MoA group G2) have been inten- against leaf spot diseases in wheat and barley, and they can be
sively developed as a promising class of modern, broad-spectrum used in cereal segments. In addition, they are very efficient against
fungicides, together with the new innovative subgroup of leaf spot diseases such as ear blight (Alternaria solani).
pyridinyl-ethyl benzamides.20 The mixture of bixafen with the triazolinthione SBI fungicide
Since 2003, boscalid (BASF) has been known as a prothioconazole (see Section 4.1) is used as Xpro®, which has a
chlorine-substituted, systemic and broad active pyridine car- broad spectrum of activity in the cereal segment and controls
boxamide fungicide in speciality crops. all major leaf spots, brown rust, as well as Fusarium species.
Some years later, a new generation of novel fluorine-substituted Fluxapyroxad is a systemic, broad-spectrum SDHI that is efficient
(e.g. R1 = F or R2 = CHF2 , CF3 ) pyrazol-4-yl-carboxamides has been against leaf spot diseases in many crops and can be used for seed
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established on the market, showing as SDHIs an evolution of treatments. In order to obtain optimal curative activity against
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Table 1. Selection of new agricultural chemicals launched between 2004 and 2014 as fungicides, herbicides and safeners, insecticides and
nematicides
Common name CAS chemical name Trade name Manufacturer Year of launch Use Sectiona
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Table 1. Continued
Common name CAS chemical name Trade name Manufacturer Year of launch Use Sectiona
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Table 1. Continued
Common name CAS chemical name Trade name Manufacturer Year of launch Use Sectiona
(Septoria tritici, Pyrenophora teres and Puccinia sp.), but it is also treatment applications against Pyrenophora spp. in cereals.
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Application rate
Common name (trade name) R1 R2 R3 (crop) (g AI ha−1 )
a Technical isopyrazam in a mixture of two syn-isomers and two anti-isomers: ratios 70:30 and 100:0.
b Vibrance®: 2.5–20 g AI 100 g−1 seed.
c Emesto fusion®: mixture of 390 g AI h−1 fluoxastrobin and 50 g AI h−1 penflufen.
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Figure 4. Agrophoric-element-based structure design of the SDHI fungicide fluopyram, influenced by fluopicolid and flutolanil.
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Figure 6. Chemical structures of the strobilurin fungicides: (a) dihydro-dioxazine such as fluoxastrobin; (b) oximino-acetamide group such as orysastrobin.
4.4 Mitosis and cell division inhibitors defence mechanism, which controls leaf blast (M. grisea), the most
Inhibitors of 𝛽-microtubule assembly in mitosis that have been serious rice disease in Japan, and bacterial leaf blight in rice.47
used as fungicides include the long-known group of methyl ben- In contrast to already existing plant defence inductors such
zimidazole carbamates such as carbendazim and thiophanate as benzisothiazole (probenazole, 1981), benzothiodiazole
fungicides such as thiophanate-methyl. However, there are sev- (acibenzolar-S-methyl, 1996) and the thiadiazole carboxamide
eral target-site mutations (mostly E198A/G/K and F200Y) in the tiadinil (2003, Nihon Nohyaku), the new isotianil possesses an
𝛽-tubulin gene described. The benzamide zoxamide is the first isothiazole moiety, which maintains a steady preventive effect of
inhibitor of 𝛽-microtubule assembly to be important for the con- the molecule, influenced by its systemic properties and low water
trol of oomycete pathogens such as Phytophthora, Pythium and solubility.
Plasmopara.40 At the cellular level, these fungicides arrest nuclear Isotianil is flexible and can be used either at sowing or as a foliar
division and destroy the microtubule cytoskeleton by a highly spe- treatment. It has a long-lasting and stable efficacy against rice
cific covalent binding to cysteine (Cys239) on the 𝛽-subunit of blast and bacterial leaf blight. No cross-resistance to any other
tubulin.41 commercial products have been observed, and therefore it has a
low risk of resistance development.
After its application to young plants, the plant is protected
4.4.1 Delocalisation of spectrin-like proteins against infection. Gene expression profiling was used to support
The benzamide fungicide fluopicolide (2006; Bayer CropScience) the MoA identification of the novel resistance inducer isotianil.
(Fig. 7) belongs to the new class of pyridinylmethyl-benzamides Upon infection, isotianil-primed plants displayed a faster and
and exhibits a high level of activity against a broad spectrum stronger induction of plant-defence-related genes in comparison
of oomycetes, such as Phytophthora infestans, P. viticola and vari- with the control (mock treated) (Fig. 8).47
ous Pythium species.42 Because of the different MoAs, it does not
show any cross-resistance to other commercial oomycete fungi-
4.6 Cellulose synthase inhibitors
cides. Fluopicolide is effective against several stages of the fungal
life cycle (e.g. the release and motility of zoospores, the germina- During the past 10 years, two further new candidates of the
tion of cysts, the growth of the mycelium and sporulation) within chemical class of carboxylic acid amide (CAA) fungicides (FRAC:
only a few minutes of application.43 It was found that this fungi- MoA group H) have been launched or under development.48 They
cide induces a rapid reallocation of the cytoskeleton-associated all belong to the cell wall biosynthesis inhibitors, interacting with
spectrin-like proteins, considered to form a bridge between the cell wall deposition and cellulose biosynthesis.
cytoskeleton and the plasma membrane. The spectrin-like pro- As the first member of the mandelic acid amide fungicides,
teins could play a role in the tip extension of fungi and the polarity mandipropamid (2006; Syngenta) (Fig. 9a) has been commer-
of hyphal elongation. Fluopicolide induces dramatic symptoms on cialised as a racemic mixture of both enantiomers. Because none
P. infestans zoospores.44 They stop swimming within a minute of of the enantiomers demonstrated a biological advantage over the
contact with fluopicolide at a concentration as low as 1 μg mL−1 , mixture, the protective and curative fungicide was registered as
and their swelling up to total lysis has been observed (Fig. 7b).43,45 racemate.49 Mandipropamide can be used for oomycete disease
Immunological studies demonstrated that a cytoskeleton- control on potatoes, such as late blight (Phytophthora infestans),
associated spectrin-like protein was delocalised after fluopicolide and on tomatoes, as well as for downy mildew control in vines.
Valifenalate (2008; Isagro) (Fig. 9b), the third member of the vali-
treatment. This happens in both zoospores and hyphae of P.
namide carbamates (benthiavalicarb, iprovalicarb), is a fungicidal
infestans.
and racemic dipeptide with activity against Phytophthora sp., Per-
As a modern fungicide, fluopicolide exhibits a high level of
onospora sp. and Plasmopara sp.48 It is suitable for application on
activity against a range of omycete diseases in different crops
crops such as grapevines, potatoes and vegetables. Finally, from
such as potato, tomato, vines, brassicas, cucurbits, lettuce, onions,
the subclass of cinnamic acid amides (dimethomorph, flumorph),
leeks, peppers, etc., and its spectrum can cover the most important
the candidate pyrimorph (ISO-proposed common name) (Fig. 9c)
genera of the orders Peronosporaceae and Pythiacae.46
is still under development by China Agricultural University.50
application rate, leads to a systemic induction of the plant’s own herbicides as well as on integrated cultivation systems. In the
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Figure 7. Structure of fluopicolide and immunofluorescence microscopic studies of (a) untreated and (b) treated zoospores and mycelium of oomycetes
(data taken from Toquin et al.43 and Jeschke45 ).
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Figure 9. Chemical structures of new carboxylic acid amide fungicides: (a) mandelic acid amides such as mandipropamid; (b) valinamides such as
valifenalate; (c) cinnamic acid amides such as pyrimorph (ISO-proposed common name).
Figure 10. Chemical structures of 4-HPPD inhibitors: (a) hydroxypyrazole group such as pyrasulfotole and topramezone; (b) cyclohexanedione group such
as tembotrione and tefruryltrione.
The first new 4-HPPD hydroxypyrazole inhibitor toprame- Both the pyrazolone hydroxyl and the benzoyl oxygen interact
zone (2005; BASF) (Fig. 10a) is used predominantly in corn for directly with the catalytic iron ion.
post-emergence applications, with application rates of 12–75 g Tembotrione (2007; Bayer CropScience) (Fig. 10b) is the latest
AI ha−1 .57 If applied in synergistic mixtures with PS II inhibitors member of the 4-HPPD cyclohexanediones, and structurally
such as atrazine or terbutylazine, most key grasses and broadleaf similar to tefuryltrione (2002; Aventis; R1 = CH2 CF3 versus
weeds in corn can be controlled. tetrahydrofur-2-ylmethyl) (Fig. 10b), for selective control of
With the second new 4-HPPD hydroxypyrazole inhibitor pyra- broadleaf weeds and annual grasses in field corn, seed corn,
sulfotole (2008; Bayer CropScience) (Fig. 10a), an active ingredient sweet corn and popcorn.61 Its application leads to a selec-
with a new MoA for broadleaf weed control in wheat and barley tive post-emergence control by rapid bleaching (depletion of
was brought onto the market. Pyrasulfotole is an innovative tool carotenoids) and elimination of susceptible broadleaf weeds
for resistance management, with excellent post-emergence use on and annual grasses in corn. The introduction of the innovative
wheat, barley and triticale.58 It is active against a wide range of 2,2,2-trifluoroethyl residue results in improved physicochemi-
broadleaf weeds, such as chickweed (Stellaria media), lamb’s quar- cal properties (water solubility 28.3 g L−1 at pH 7) that permit
ters (Chenopodium album), nightshades (Solanum spp.), pigweeds easy translocation of hydrophilic (aqueous) and lipophilic
(Amaranthus spp.) and velvetleaf (Abutilon theophrasti). The appli- (waxy, fatty) barriers on the weed surface to the target sites
cation rates of 25–50 g AI ha−1 provide reliable weed control, espe- in plant cells. By application with the safener (see Section 6)
cially in mixtures with the PS II inhibitor bromoxynil (Fig. 11). isoxadifen-ethyl (Laudis® OD: adjuvant system in an oil dispersion
The lipophilic 4-CF3 -phenyl moiety in pyrasulfotole shows a as a ‘ready-for-use product’), corn can be protected from herbicide
binding preference for the hydrophobic niche of the open confor- stress and demonstrates tolerance even under very challenging
mation of the 4-HPPD target enzyme, as outlined in Fig. 12.56,59 growing conditions.
The crystal structure shows the active site of 4-HPPD, with its
iron atom located within an open twisted 𝛽-sheet formed by 5.2 Protoporphorinogen-IX-oxidase (PPO) inhibitors
seven 𝛽-strands. This iron is octahedrally coordinated by two The inhibition of protoporphyrinogen-IX-oxidase leads to accu-
histidines (His), one glutamic acid (Glu) residue, a well-defined mulation of the enzyme product protoporphyrin IX. Light induces
water molecule and an inhibitor oxygen atom that is presumed to protoporphyrin IX to generate large amounts of singlet oxygen,
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take the position of the substrate’s oxygen in the transition state.60 leading to the peroxidation of the unsaturated bond of the
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Figure 11. Kochia scoparia treated post-emergently with pyrasulfotole (A), bromoxynil (B) and a combination of pyrasulfotole and bromoxynil (C). The
herbicides were applied with the recommended field dose. Pictures were taken 21 days after treatment.
Figure 12. Pyrasulfotole and its molecular interaction with the herbicide
Figure 14. Structures of pinoxaden and pinoxaden acid.
target 4-HPPD. Octahedral coordination of the iron at the active site of
4-HPPD (data taken from Freigang et al.56 ).
5.3 Acetyl CoA carboxylase (ACCase) inhibitors
Acetyl CoA carboxylase (ACCase; EC 6.4.1.2), crucial for the
metabolism of fatty acids, is a biotin-dependent carboxylase that
produces malonyl-CoA from bicarbonate as a source of carboxyl
group, and ATP as a source of energy.65,66 Besides the known
ACCase active herbicide classes cyclohexanediones (CHDs) and
(R)-configurated (het)aryloxyphenoxypropionates (AOPPs),67 the
phenylpyrazolinone pinoxaden (2006; Syngenta)68 (Fig. 14) was
developed as proherbicide (R = CO-tert-Bu)69 for the selective
Figure 13. Saflufenacil. post-emergence control of key annual grass weeds in cereals.
Pinoxaden also shows activity against several ACCase-
inhibitor-resistant biotypes but does not control all of them.
fatty acids found in cell membranes.62 With the success of It can be applied from the two-leaf stage up to the flag leaf stage
herbicide-resistant crops and the possibility of post-emergence of annual grasses and shows a weed spectrum that covers a
applications combined with relatively low herbicide costs, com- wide range of important annual grass species such as blackgrass
bined with the perceived advantage of applying a herbicide only (Alopecurus myosuroides), silky bentgrass (Apera spica venti), wild
when weed growth was observed, the end of residual herbicides oats (Avena spp.), ryegrass (Lolium spp.), canary grass (Phalaris
was prophesied to have arrived a while ago.63,64 Today, the situ- spp.), foxtails (Setaria spp.), meadowgrass (Poa spp.) and other
ation has changed with the appearance of glyphosate-resistant monocotyledonous weed species in cereals.70
weeds such as Amaranthus tuberculatus and Amaranthus palmeri. Pinoxaden is hydrolysed very rapidly in soil or plants, form-
The demonstrated advantage of using pre-emergence herbicides ing the vinylogous ‘pinoxaden acid’ (R = H) under aerobic,
to reduce these highly resistant weeds led to the development aerobic-anaerobic and sterile-aerobic conditions as a herbici-
of the new PPO inhibitor saflufenacil (2010; BASF) (Fig. 13), dally active metabolite (see also Section 7.3).69 Its tolerance in key
which can be used alone or in mixtures with glyphosate and cereal crops (wheat, barley) under adverse climatic conditions is
applied preplanting for burndown applications in glyphosate- obtained by incorporating the proprietary safener (see Section 6)
and ALS-tolerant crops. cloquintocet-mexyl into an easy-to-use liquid formulation, which
Saflufenacil primarily controls dicotyledenous weeds. For delivers maximum performance of pinoxaden when used with a
example, it can be used as a pre-emergence treatment in corn specially optimised adjuvant.
and sorghum (Sorghum bicolor) to control major broadleaf
weeds without triazine herbicides. If further weed shifts are 5.4 Cellulose biosynthesis inhibitors (CBIs)
observed in genetically modified crops, new market opportuni- Indaziflam (2011; Bayer CropScience) (Fig. 15) belongs to the alky-
ties might open up for herbicides with other MoAs such as PPO lazine class and inhibits the synthesis of crystalline cellulose fibres,
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inhibitors. which are necessary for plant cell wall stability.71 The exact target
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site is not yet known, but the phenomological MoA is disaggre- cyprosulfamide, and with other herbicidal active ingredients. In
gation of ‘rosettes’, which are responsible for the ordered poly- herbicides prepared for post-emergence use, thiencarbazone-
merisation of phosphorylated oligo-sugars [𝛽-(1,4)-glucan chain] methyl is coformulated, for example, with tembotrione (2007;
to cellulose fibres, the so-called microfibrils (Fig. 15).72 Bayer CropScience) (see Section 5.1) (Fig. 10b).
Because of two chirality centres in the (1R,2S)-2,3-dihydro-2,6- Today, the large sulfonylurea herbicide subclass contains more
dimethyl-1H-inden-1-amine fragment of the molecule, its than 30 members, of which only two have been launched in the
large-scale preparation needed a high degree of innovation past 10 years.74 The first sulfonylurea tritosulfurone (2005; BASF)
in manufacturing. Indaziflam shows a broad-spectrum weed (Fig. 16b) was developed for broadleaf weed control in winter
control for annual grasses and broadleaf weeds in established and spring wheat and maize. It is a broad-spectrum herbicide
permanent crops such as tree plantations, perennial crops such as with some reported activity against cleavers (Galium aparine).
sugar cane and turf grasses. Tritosulfuron (25%) is approved as a premix together with the
Indaziflam manages weed populations resistant to other MoAs growth-regulating auxin herbicide dicamba (50%) under the trade
such as EPSPS, ALS and PS II, with application rates of 73–95 g name Arrat® for the control in wheat and maize fields of broadleaf
AI ha−1 , and provides a control of weeds for up to 90 days or weed species such as wild bishop (Bifora radians), milk thistle
longer after treatment. In order to expand the spectrum of weed (Silybum marianum), common cocklebur (Xanthium strumarium)
control, it can be mixed with other herbicides such as metribuzin and black nightshade (Solanum nigrum).
and isoxaflutole. The second new sulfonylurea orthosulfamuron (2006; Isagro)
(Fig. 16b) is recommended for early post-emergence broadleaf,
5.5 Acetolactate synthase (ALS) inhibitors sedge and aquatic weed control (Echinochloa species, for example)
The four herbicide subclasses (a) triazolopyrimidine in rice, with an excellent ecotoxicological profile. The compound is
sulphonamides,73 (b) sulfonylureas,74 (c) sulfonylaminocarbonyl- formulated as 50% wettable granules.
triazolinones and (d) imidazolinones75 are efficient inhibitors of The novel sulfonylanilide pyrimisulfan (2010; Kumiai) (Fig. 17)
ALS, as the key enzyme in the biosynthesis of branched amino with divergent ALS inhibitor structure has been developed as
acids such as leucine (Leu), isoleucine (Ile) and valine (Val). Inhibi- herbicide for paddy fields.
tion of amino acid production subsequently inhibits cell division The herbicide shows good efficacy against a wide range of
and causes death in susceptible plants. weeds such as Echinochloa spp., sedges, broadleaf weeds and
Penoxsulam (2004; Dow AgroScience) (Fig. 16a) was originally sulfonylurea-resistant weeds. Furthermore, pyrimisulfan also has
designed for use in rice fields and can be used for broad-spectrum good efficacy against troublesome perennial weeds, such as
control of broadleaf weeds such as barnyard grass (Echinochloa seaside bulrush (Bolboschoenus maritimus), spikerush (Eleocharis
crusgalli), young water grass (Paspalum dilatatum) and wild buck- kuroguwai) and threeleaf arrowhead (Sagittaria trifolia). Because
wheat (Polygonum convolvulus) and important weeds in turf, retail of its relatively low soil adsorption and high water solubility
market segments and cereal crops.76,77 Penoxsulam is a systemic, compared with other rice herbicides, a controlled-release for-
phloem and xylem mobile herbicide that is absorbed via leaves, mulation (6.7 g AI kg−1 granules) was developed for use as a
shoots and roots. The herbicide can be translocated in plants one-application herbicide and effective tool for rice cultivation in
to meristematic tissue. A key attribute of penoxsulam is excel- Japan.80 The pyrimisulfan granule formulation can be applied at
lent post-emergent control with residual activity on white clover pre-emergence to the three-leaf stage of rice and exhibits consis-
(Trifolium repens), ground ivy (Glechoma hederacea) and dollar tent efficacy under simulated overflow conditions.
weed (Hydrocotyle spp). It provides herbicidal efficacy at low use
rates (6–70 g AI ha−1 ) compared with the higher rates of the most 5.6 New auxin mimics and herbicides
commonly used turf herbicides, such as 2,4-D, dicamba, MCPP and The plant hormone auxin regulates plant growth (PGR) and
triclopyr. development.81 Auxin acts by binding the F-box protein transport
Pyroxsulam (2008; Dow AgroSciences) (Fig. 16a), the latest inno- inhibitor response 1 (TIR1) and promotes the degradation of the
vation from the subclass of trazolopyrimidine sulfonamides, pro- auxin/indole-3-acetic acid (Aux/IAA) transcriptional repressors.
vides broad-spectrum control of annual grasses and broadleaf In this context, efficient auxin binding requires assembly of an
weeds, with some activity on certain perennial species.78 For auxin coreceptor complex consisting of TIR1 and an Aux/IAA
example, it is active against annual grasses and broadleaf weeds, protein. As recently demonstrated, combinatorial interactions of
with application rates of 9–15 g AI ha−1 , and its crop selectivity auxin signalling F-box proteins (AFBs) and 29 Aux/IAA proteins in
in wheat, rye and triticale varieties (hybrids of wheat and rye) is Arabidopsis thaliana may result in many coreceptors with distinct
possible in combination with the safener cloquintocet-mexyl (cf. auxin-sensing properties, and the AFB5-Aux/IAA coreceptor selec-
ACCase inhibitor pinoxaden, Section 5.3). tively binds the auxinic herbicide picloram by interaction with the
As a new member of the subclass of sulfonlyaminocarbonyl- carboxylic functional group.82
triazolinones, the herbicide thiencarbazone-methyl (2008; Bayer Classified synthetic auxin mimics (HRAC: MoA group O) such as
CropScience) (Fig. 16c) demonstrates a selective activity against phenoxy-carboxylic acids (2,4-D), benzoic acid (dicamba), quino-
perennial grasses such as johsonsongrass (Sorghum halapense) linecarboxylic acid (quinclorac) and pyridine-carboxylic acids (e.g.
and Elymus repens, together with control of problem weeds such picloram, clopyralid, aminopyralid) (see Fig. 19)83 induce physio-
as Polygonum convolvulus and suppression of Cirsium arvense and logical and phenotypic effects similar to those induced by the nat-
Convolvulus arvensis primarily in corn. ural plant hormone IAA.
It shows cross-spectrum activity against annual grasses and The auxin mimic halauxifen-methyl (ISO-proposed common
broadleaf weeds and can be applied at pre-emergence and name) (Fig. 18) was launched in 2014 by Dow AgroSciences
post-emergence timings. To overcome inherent selectivity as prodrug methyl pyridine-carboxylate for use in cereals and
in corn,79 thiencarbazone-methyl is always combined with other crops, which can be metabolically converted in plants and
445
safener technology (see Section 6), such as the novel safener soil into the pyridine-carboxylic acid halauxifen by enzymatic
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www.soci.org P Jeschke
Figure 15. MoA of indaziflam: 𝛽-(1,4)-glucan chain is transformed into cellulose microfibril (data taken from Cosgrove72 ).
Figure 16. Chemical structures of the ALS inhibitor subgroups: (a) triazolopyridines such as penoxsulam and pyroxsulam; (b) sulfonylureas such as
tritosulfuron and orthosulfamuron; (c) sulfonylaminocarbonyl-triazolinones such as thiencarbazone-methyl.
cides can be combined with a safener for crop protection and flowering.88
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Figure 18. Chemical structures of the auxin mimic herbicides picloram, clopyralid and aminopyralid and the prodrug halauxifen-methyl. The latter can
be converted in plants into halauxifen by enzymatic hydrolysis.
successfully controlled by these nAChR competitive modulators, and is a resistance management tool for sustainable pest control.
Pest Manag Sci 2016; 72: 433–455 © 2015 Society of Chemical Industry wileyonlinelibrary.com/journal/ps
www.soci.org P Jeschke
Figure 20. Chemical structures of the neonicotinoids imidacloprid (IMD), thiamethoxam (TMX) and clothianidin (CLT).
marker genes in barley is delayed; (ii) photosynthesis-related ryanodine-sensitive Ca2+ release channel. It regulates the
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Figure 22. Molecular docking studies of flupyradifurone within the CYP6CM1vQ (B. tabaci) cavity model: representative flupyradifurone pose in
surroundings of amino acids.
crop utility because of its fast-acting and long-lasting effect and ity and demonstrates broad activity against a wide range of insects,
Pest Manag Sci 2016; 72: 433–455 © 2015 Society of Chemical Industry wileyonlinelibrary.com/journal/ps
www.soci.org P Jeschke
Figure 25. Phthalic acid and anthranilic acid diamides as RyR modulators such as the lead structures flubendiamide, chlorantraniliprole and cyantranili-
prole as well as the development candidates tetraclorantraniliprole, cyclaniliprole and tetraniliprole (ISO-proposed common names).
including chewing and sucking insects, as well as coleopteran CropScience) (Fig. 26). All so-called ‘ketoenoles’ (KTEs) are ACCase
pests. inhibitors and inhibit lipid (or fatty acid) synthesis, but they have
In 2013, the three RyR modulators flubendiamide, chloran- completely different physicochemical properties and address
traniliprole and cyan-traniliprole demonstrated fast-rising sales, different biological spectra. Whereas spirodiclofen is non-systemic
with a global turnover of over $US 1.4 billion, representing approx- with long-lasting activity against spider mites (only via contact
imately 8% of the insecticide market.89 activity), spiromesifen has translaminar activity against spider
Besides tetrachlorantraniliprole (Si Lv Chong Xian An, 2013; mites and is an important tool for whitefly insecticide resistance
SYRICI) outlined in Fig. 25 with R1 = Me, R2 = Br and R3 , R4 , management (IRM).
R5 = Cl, which was marketed only in China, further new com- As a prodrug,69 the insecticide spirotetramate (R = CO-O-Et)
pounds are currently under development by Ishihara and demonstrates a broad activity against aphids and other
Bayer CropScience, exemplified by cyclaniliprole (R1 = CHMe- sucking pests because of the ambimobile behaviour of the
cyclopropyl; R2 , R3 = Br; R4 = Cl; R5 = H) and tetraniliprole (R1 , spirotetramate-enol (R = H) (Fig. 26). In contrast to IMD,
R3 = Me; R2 = (5-CF3 -2H-tetrazol-2-yl)methyl; R4 = CN, R5 = H) spirotetramat-enol (R = H) is also translocated over a longer
(ISO-proposed common names). distance via the phloem stream, and thus shows basipetal and
Recently conducted baseline studies and resistance monitor- acropetal transport, also dubbed two-way systemicity. After appli-
ing campaigns confirmed the regional development of diamide cation, the whole of the plant, including the roots, is protected. As
insecticide resistance appearing in the field in a few pests such a result, spirotetramat (R = CO-O-Et) has excellent activity against
as diamondback moth (P. xylostella),112 tea tortrix (Adoxophyes difficult-to-control sucking pests such as the woolly apple aphid
honmai)113 and tomato leafminer (Tuta absoluta),114 but resis- (Eriosoma lanigerum).
tance ratios vary between species.115 Mutations in the C-terminal
membrane-spanning domain of the Plutella RyR were described,
influencing the binding of diamide insecticides, e.g. amino acid 8 NEMATICIDES
substitutions G4946E,116 I4790M and Q4594L117 respectively. Plant-parasitic nematodes (PPNs) such as the root-knot nema-
These investigations will provide an important tool for resistance tode (Meloidogyne spp.), cyst nematodes (Globodera spp. and
management and deployment of suitable rotational applications. Heterodera spp.) and migratory nematodes (Radopholus spp.,
Pratylenchus spp. and Helicotylenchus spp.) infest many important
7.4 Acetyl CoA carboxylase (ACCase) inhibitors agricultural crops, such as soybean, coffee, potato, sugarbeet,
The acetyl CoA carboxylase (ACCase; EC 6.4.1.2), crucial for the corn, banana, etc., and they are responsible for approximately
metabolism of fatty acids, is a biotin-dependent carboxylase that 12% of world crop production losses (http://plpnemweb.
produces malonyl-CoA from bicarbonate as a source of carboxyl ucdavis.edu/nemaplex/Plntpara/damage.htm; over $US 100
group, and ATP as a source of energy.118,119 billion per year). Besides damaging roots, they can also transmit
After the successful introduction of the two tetronic acid viruses and make plants more vulnerable to attack by bacterial
derivatives spirodiclofen (2002) and spiromesifen (2004), 5 years and fungal pathogens in the soil. PPNs have been controlled
450
later Bayer CropScience launched spirotetramate (2009; Bayer through extensive application of the fumigant nematicide methyl
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Figure 26. The prodrug spirotetramate (R = CO-O-Et) forms spirotetramate-enol (R = H) by O-deacylation in the plant tissues.
duced, such as the fluoralkylthioether fluensulfone (Adama)123 and cations and as a perfect option for mixtures with complex III
Pest Manag Sci 2016; 72: 433–455 © 2015 Society of Chemical Industry wileyonlinelibrary.com/journal/ps
www.soci.org P Jeschke
inhibitors such as the strobilurins. With isotianil, a novel plant 12 Gisi U, Assessment of selection and resistance risk for demethylation
defence inducer could be developed to initiate systemic induc- inhibitor fungicides in Aspergillus fumigatus in agriculture and
medicine: a critical review. Pest Manag Sci 70:352–364 (2014).
tion of the plant’s own defence mechanism that controls rice 13 Tala F and McDonald BA, Significant variation in sensitivity to a
diseases. Further optimised herbicide classes such as 4-HPPD DMI fungicide in field populations of Fusarium graminearum. Plant
and ALS inhibitors can be applied at much lower application Pathol 64:664–670 (2015).
rates. To overcome inherent selectivity of herbicides in spe- 14 Jautelat M, Elbe HL, Benet-Buchholz J and Etzel W, Chemistry of proth-
ioconazole (JAU 6476). Pflschtz-Nachr Bayer (Engl Edn) 57:145–162
cial crops such as corn, safener technology has been further
(2004).
intensified (e.g. the combination of thiencarbazone-methyl with 15 Mauler-Machnik A, Rosslenbroich HJ, Dutzmann S, Applegate J and
cyprosulfamide). Research of highly specific ryanodine receptor Jautelat M, JAU 6476 – a new dimension DMI fungicide. Proc
modulators, demonstrating similar symptoms to those identi- Brighton Crop Protection Conf – Pests and Diseases, BCPC, Farnham,
fied in insects treated with the toxic plant alkaloid ryanodine, Surrey, UK, pp. 389–394 (2002).
16 Häuser-Hahn I, Baur P and Schmitt W, Prothioconazole – a new
resulted in the discovery of a new class of insecticides with novel dimension DMI. Biochemistry, mode of action, systemic effects.
MoAs (e.g. flubendiamide, chlorantraniliprole). The pyridinyl-ethyl Pflschtz-Nachr Bayer (Engl Edn) 57:237–248 (2004).
benzamide fungicide fluopyram, combining a good safety pro- 17 Dutzmann S and Suty-Heinze A, Prothioconazole: a broad spec-
file with a significant increase in yield and quality in a broad trum demethylation-inhibitor (DMI) for arable crops. Pflschtz-Nachr
Bayer (Engl Edn) 57:249–264 (2004).
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increasing importance. These beneficial effects are sometimes drogenase inhibitor fungicides in Botryotinia fuckeliana (Botrytis
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