519 This review will 15 This article is a US Government work and is in the public domain in the USA Published online in Wiley Online Library: 9 January 2012 Correspondence to: Franck E Dayan, UnitedAgricultural States Department Research of Service, Agriculture, Natural ProductsBox Utilization 8048, University, Research MS 38677, Unit, USA. PO E-mail: [email protected] United States DepartmentUniversity, MS, USA of Agriculture, Agricultural Research Service, ∗ discuss the potential benefitnatural of products as research sources programs ofmechanismsofherbicidalaction.Focuswillbeplacedonsuccessful new focusing herbicide on structures and new natural-product or natural-product-like herbicides, and this will be extended to include recent discoveries thatnatural validate the products view may that playdiscovery. an important role in future herbicide 2 ADVANTAGESURAL AND PRODUCTS LIMITATIONS OF NAT- Utilizing natural products for the discovery of new herbicides offers a number of advantages, but itare is far a from number being a ofsuch panacea. compounds There problems for or large-scale weed limitations managementcompound has (Table associated all 1). of with the No limitations or using advantagesbut listed in the Table listed 1, traits are generalizationscompounds. that apply to many natural compounds used for weed management. However, as theof number cases of herbicide-resistant weeds continuesis to a increase, there need forthere new is chemical classesof a of action pressing herbicides. and In need particular, new for molecular compounds target with sites. new modes 11 www.soci.org Companies 1 Chrysanthemum Accepted article published: 12 October 2011 More recently, the 9 There are only a handful root led to the identification 12–14 2–8 Daniel K Owens and Stephen O Duke ∗ Derris elliptica 68: 519–528 As of 2004, approximately 11% of global sales of 2012; 10 natural products; microbial toxins; allelochemicals; mode of action

Natural-product-based discovery has been the least successful Natural products also have a history of use as pest management agricultural pesticides are either naturalthat products trace or their discoveries compounds back to bioactive natural products. discovery of botanical insecticidal powders from spp. flower heads and of pyrethrum and rotenonehowever, respectively. had Natural less of products an impact have, on modernon pest management medicine. than have such enthusiasm for thisadopted type chemical of chemistry discovery that strategieslikeness’ many of to have molecules channeled optimize in the high-throughputcombinatorial screens synthesis ‘natural and programs. Pest Manag Sci 1 INTRODUCTION The therapeutic propertiesbenefited of humankind bioactive since naturalthe prehistoric products ‘western times. have medicine’ era, Atplants chemists the and began discovered analyzing onset numerous medicinal of digitoxin, active ingredients morphine, (e.g. quinine aspirin, tremendous and artemisinin) impact that on80% still of human pharmaceutical have drugs health. a haveproducts been and Today, analogs generated derived from from approximately natural natural products. Keywords: Abstract Weeds continue to evolve resistancebeen commercialized to in all nearly 20 the years. known Thethat so-called modes have ‘new the of chemistries’ are same herbicidal simply mechanisms molecules action, of belonging actionsaflufenacil but to as new no or older chemical herbicides classes herbicide the (e.g. with the very-long-chain protoporphyrinogen-oxidase-inhibiting a fattynumber pyrimidinedione new acid of target elongase tools site targeting to has sulfonylisoxazoline manageThere herbicide weeds, is pyroxasulfone). and Therefore, an in the imminent particularsites those need not that for previously can truly exploited controlapproach innovative by herbicide-resistant to weeds, herbicide older classes discovery is active of that diminishing ingredients. capitalizescompounds. herbicides rapidly. on This The that the review structural natural explore diversity proposes process chemical andtarget a ingenuity of sites spaces afforded rationale over extended-throughput by and long for these screening periods interact biologically a of (highto active times) with natural-products-centered number that interact target has of with shaped compounds the specificnatural evolution tested and of target on natural synthetic sites. products phytotoxins, many tends and As to potential the more generate pharmaceutical this emphasis molecules industry review tailored should to solve be shows, problems placedPublished in there 2012 on the by applying agrochemical is John industry. methods Wiley generally that & have Sons, little Ltd. proved overlap beneficial between to the mode of action of to herbicide discovery Franck E Dayan, Rationale for a natural products approach (wileyonlinelibrary.com) DOI 10.1002/ps.2332 Review Received: 26 September 2011 in the area of weed management. tools. Many treatises on agricultural practices published by ancient Greek and Roman scholarsVergil, (e.g. Columella Theophrastus, Cato and the Plinyof Censor, essential the oils Elder) for mentionplant pest species were the control. known to In application have pesticidal theShengnong properties Far during Ben the East, Tsao more Jing than era 200 (AD 25–220). of examples of either natural products or natural-product-like No No No No No No No No No No No Yes Yes 68: 519–528 2012; there is no reason Nevertheless, if the 1 22 86 49 68 75 81 79 69 41,42 53,54 18 19–21 Patent for herbicide use Commercialized FE Dayan, DK Owens, SO Duke Pest Manag Sci No No No No New Yes New No action Mode of -glucitol New No Relevant information on the natural products mentioned in D While the problem of rediscovery is still an issue, new Finally, registration of natural products for pest management Syringomycin Macrocidin CyperinActinoninPhaseolotoxinHydantocidinRibofuranosyl triazoloneAlbucidin NewAnhydro- New New New New No No Yes No Yes NewCinnacidinAscaulitoxin No Plant source No No NoBOA/DIMBOAPelargonic acid New NewCitral No New No New No Yes Yes No New Yes Table 2. the text Compound Microbial source Thaxtomin A New Yes Sarmentine New Yes Tentoxin Pyridazocidin number of natural products currentlybe patented used for as drug an use indicationto can of obtain the such pharmaceutical intellectual industry’s rights ability protection, 3 NATURALOF PRODUCTS HERBICIDES AS SOURCES 3.1 Bialaphos (bilanophos)The and glutamine synthetase topicwithout of featuring the success natural-product story of phosphinothricin4-(methylphosphinato)butanoate] herbicides [2-amino- (Fig. 1). cannot Both phosphinothricin (glufosinate) be and covered bialaphos (a tripeptide analog) are broad- product target sitesof may action be owing to unsuitable lackphytotoxins tagetitoxin for of and carbocyclic specificity. a coformycin inhibit For nucleic herbicidal example,acid the mode synthesis microbial by distinctconcerns mechanisms. about This their raisesthe toxicological suitability mammalian for toxicityfumonisins weed of and management. AAL-toxins) ceramide Also, highly is synthase phytotoxic classes problematic of inhibitors for compounds. (e.g. these otherwise instrumentation enablesproducts the directly in rapid crudepure compounds. extracts identification These or dereplicative tools from of circumventonce what minute the was natural amounts costly of isolating and previously known time-consuming molecules. process of purifying and in the Unitedthe States registration process benefits less expensive from andbiopesticide category. more a However, protection rapid of special under intellectual rights the of tracknatural products that may makes sometimes beis limited, a which concern undoubtedly for the agrochemical industry. to believe that thecounterpart. same would not be true for its agricultural they are 17 However, the This article is a US Government work www.soci.org and is in the public domain in the USA 16 -hybridizedcarbonsthan 3 may be too expensive to synthesize problems optimized for activity but have inadequate physicochemical properties compounds is costly, and sourcing may be limiting half-life limited Complicated structures that Structure may already be Rediscovery of known Excessively short environmental Advantages and limitations of using natural products as a extending to unexplored chemical spaces increases the likelihood of discovering relevant structures makes identification easier and requires smaller amounts friendly One of the indirect and important benefits of the chemical The propensity of nature to have selected biologically active There has been a dearth of truly innovative chemical classes of The structurally elaborated architecture of natural products New structural backbones Table 1. source of new herbicides or new modes of action Advantages Limitations New molecular target sitesEvolved biological activity May have high general toxicity Improved instrumentation Generally environmentally Better public acceptanceMaybecheapertoregister Patentprotectionmaybe Public expects low-rate use synthetic compounds. They may also contain sulfate orgroups, phosphate whereas halogenation is uncommon. composition and structural(e.g. characteristics the of absence naturalamount of of products ‘heavy’ ‘unnatural’ atoms)rapidly is ring degraded that in most structures the ofthe and natural these perception environment. compounds the that This are mostbenign. low accounts natural However, for products this arenatural is environmentally products. possibly Their one physicochemicalthan of ideal properties for uptake the may into and translocation Achilles’ be in plantsadequate less heels to effect produce at an of an economical dose. Thenatural rate products of may also degradation be of too rapid toas allow successful their herbicides. development molecules is not without other limitations, as many natural- more likely toTable interact 2. This with is important newguidelines because in the target the United States new no longer sites, pesticide consider the registration toxicological potential as of pesticides illustrated individually, but in ratheraggregate evaluate exposure the risk of of sites entire of action. classes Furthermore, evolution of of resistancecurrently pesticides to available most with herbicides of makes the similar the discoveryaction of a new sites particularly of pressingand issue farmers. for agrochemical companies wileyonlinelibrary.com/journal/ps herbicides in thebackbone past structures two decades. inof Including discovery strikingly natural-product programs uniquenatural ensures scaffolds products for a are future source oxygen-possessmorestereogeniccentersandsp development. and nitrogen-rich Indeed, molecules that evolved over eons tofavors address the specific discovery biological of stresses,compounds biologically which explore active compounds. traditionally As unchartedcomparison these chemical with spaces conventional in synthetic molecules, structural complexity of manythe drawbacks natural of these products molecules. may Thesynthesis costs be associated for with one their agricultural of issue use is less may critical be for the prohibitive, pharmaceutical industry. whereas this

520 521 32,33 Me 2 SO OH OH 29 O O Cl Modeling of the bind- Protein phosphatases spp.) and the Spanish O 30 OH 34,35 O O O Endothall 2 O Sulcotrione Cinmethylin O Epicauta NH O Leptospermum scoparium)isrich wileyonlinelibrary.com/journal/ps O P Phosphinothricin O O O HO ). Cantharidin and its cantharadic acid (2,3- O O O O Cantharidin O 1,4-cineole -triketones (e.g. leptospermone, grandiflorone and β Leptospermone The natural herbicide phosphinothricin and the similarity O A number of other natural products also inhibit HPPD. www.soci.org 31 The essential oil of manuka ( Figure 1. mechanism. Inhibition of HPPD stops the synthesissate, of which homogenti- is a key precursorand of tocotrienols) the and prenyl tocochromanols quinones. (tocopherols One of the prenyl quinones, plastoquinone, is an essentialactivity. cofactor In for the phytoene absenceactivity desaturase of is plastoquinone, interrupted. phytoenemimicking desaturase inhibition Bleaching of phytoene of desaturase. the green tissues ensues, 3.3 7-Oxabicycloheptane-2,3-dicarboxylicand protein phosphatase acidCantharidin herbicide (2,6-dimethyl-4,10-dioxatricyclo-[5.2.1.0]decane-3,5- dione) (Fig. 1) isterpenoid a from the potent blister toxin beetlefly ( produced (Lytta as vesicatoria adimethyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic natural defense acid) ana- log are strong inhibitors of serine/threonine protein phosphatases (PPP) in both animal and plant systems. between somecommercial natural herbicides (right). products (left) and their structurally related ing of these triketones (and additional analogs)uation to of HPPD and the eval- hydrophobicinteractions) contribution demonstrated with that the HINT substrate-binding (hydropathic domainHPPD consists of of a lipophilic region that favorstones the binding with of trike- long hydrophobic sidetails. chains over those with shorter in balance with theirrylation kinase status, counterparts and control therebysuch the the functions phospho- as activity, signal of transduction pathwaysgene proteins and expression. involved regulation This of in control canphysiological lead processes. to effects on a number of in natural flavesone). This oil also causes bleaching of plants. Leptospermone is a good inhibitor of HPPD, but grandiflorone (aof minor the component oil) is a much better HPPD inhibitor. 26 and is While no Bialaphos ). spp.). This However, a 24 25 23 This article is a US Government work and is in the public domain in the USA 26,27 -lactam (see the review by β p-hydroxyphenylpyruvate pathovars produce tabtoxin, a Streptomyces hygroscopis 68: 519–528 ). In that report, triketone herbicides were obtained 24 p-hydroxyphenylpyruvate dioxygenase (HPPD) as 28 -lactam-linked dipeptide proherbicide. This natural 2012; Pseudomonas syringae Inhibition of this enzyme disrupts the biosynthesis of Prior to the discovery of the triketone herbicides, all herbicides Glutamine synthetase is required for the production of Bialaphos is an especially unique inhibitor in that its phos- Natural products for herbicide discovery (sometimes called bilanophos)cultures is of obtained themarketed from as actinomycete a herbicide fermentation in eastern Asia. Bialaphosthatisbioactivatedintophosphinothricinbyplantsbeforeexerting is a proherbicide its herbicidal action. The organismamountoffreephosphinothricin.Glufosinate,thesyntheticformof also directly produces a small phosphinothricin, is produced as a herbicide by chemical synthesis in the rest of the world (reviewed by Duke and Dayan different report suggests that the discoveryserendipitous. may have been more Pest Manag Sci spectrum post-emergence herbicides that can bea used to wide control range of weeds in agricultural settings. carotenoids and causesfoliage bleaching similar (loss to that ofsaturase observed (e.g. chlorophyll) with norflurazon), inhibitors of but of this the phytoene activity occurs de- via a different other herbicide has beenber developed for of this other targetexample, natural site, a products num- have the same target site. For tabtoxinine-β product is bioactivated via cleavage ofnine, its releasing peptide the bond toxin to tabtoxinine- threo- from a program aiming toinhibiting discover new herbicides. acetyl-CoA-carboxylase- Regardlessherbicides of are their structurally origins,counterparts similar the produced in to triketone nature. their phytotoxic triketone that caused bleaching of foliage inhibitedkey phytoene desaturase, enzyme a in carotenoid synthesis.class However, this had new no chemical directreport effect on on the phytoene activity desaturase.ylase of suggested similar A that compounds fortuitous this on newenzyme tyrosine in class plants. hydrox- To of test this hypothesis, herbicide the effect maytyrosine of triketones levels inhibit on in this rats was examined, butnot tyrosine inhibited. hydroxylase Another potential was target, tyrosine aminotransferase, was subsequently eliminated as well. Continuedidentification efforts of led to the the target site of triketones in animals.afterwards This validated enzyme as target a site new was herbicide mode of action in plants. 3.2 Triketonedioxygenase herbicidesThe and discovery of triketonebecause herbicides two is differing somewhat accounts controversial haverecalls scientists in been California identifying published. the already One known natural triketone story leptospermone (Fig.an 1) allelopathic as plant themolecule called caused active bottlebrush bleaching of (Calistemon componentthe plant triketone of tissues, backbone supposedly and led to optimization the of commercial development triketone of herbicides the (e.g. sulcotrione). glutamine and, perhapsdetoxification. even Inhibition more of this importantly, enzymethe cellular results for pool in of ammonia glutamine a and an reductionlevels. increase in in This ammonia interrupts to photosynthesis toxic andfew leads days. to death within a phinothricin moiety possessesP-methylated amino a acid C–P–C isand a acts structural bond. as analogue This of an glutamate inhibitor unusual of glutamine synthetase. Duke and Dayan ENR is -formyl species, 48 N 68: 519–528 -helices. 2012; α 43 -dependent enzyme Streptomyces Peptide deformylase + This mode of action is It is an inhibitor of the 50 Structure–activity studies 44 49 FE Dayan, DK Owens, SO Duke 41,42 Pest Manag Sci -formyl group from and other N ENR is an NAD 47 45 seedlingstreatedwiththaxtominAhavelower -sheet surrounded by seven β Streptomyces scabies However, cyperin has a different mechanism of action, 46 Typical phenotypic responses of plants exposed to thaxtomin Actinonin was thought to be exclusively active on prokaryotes the causative agents of common scab diseasetaproot in crops. potato and This other herbicidebut has has yet been to patented be as commercialized. a herbicide is a criticalprokaryotes enzyme by because removing it the initiates protein translation in different from that of known cellulose-biosynthesis-inhibiting her- bicides such as dichlobenil and isoxaben, althoughof the the symptoms plants are similar. determined that the presence of a 4-nitroindole group isto necessary maintain phytotoxicity of these metabolites. the molecular target site ofcommonly the used diphenyl as ether a triclosan componentenzyme which of is is not antimicrobial the primary soaps, target but site of this any commercial herbicide. 4.1.3 Actinonin andActinonin peptide deformylase (Fig. 2)pseudopeptide produced is by soil a actinomycetes.has This compound naturally beenproduct occurring patented has been hydroxamic for developed acid to herbicide date. use, but no commercial 4.1.2 Cyperin andA plant number enoyl of (acyl fungal plant carrier pathogens protein) produce reductase cyperin, anatural phytotoxic diphenyl ether that causesdegradation. light-independent Diphenyl membrane ethers havecompounds been used a to resourceful develop groupdifferent modes commercial of of herbicides action. Some with diphenylporphyrin ether three herbicides synthesis inhibit byothers inhibiting are protoporphyrinogen potent oxidase; inhibitors ofinhibits acetyl-CoA carboxylase; phytoene aclonifen desaturaseoxidase. as well as protoporphyrinogen 4.1.1 Thaxtomin AThaxtomin and cellulose synthesis A (Fig.produced 2) by is a phytotoxic cyclic dipeptide analog A include reduced seedling growth, cellof swelling cell and walls. lignification Biochemically, thaxtomin inhibitsArabidopsisthaliana cellulose synthesis. crystalline cellulose and higher contentslulose of in their pectins cell and wall, hemicel- relativepanied to with untreated plants. an This alteration is of accom- primary and the secondary expression cellulose synthesis, of as well genes asated involved genes with associ- pectin in metabolism and cell wallA remodeling. affects the Thaxtomin formation of the cellulose synthaseoutside complexes of on the the plasma membrane, leadingthe to cortical its dissociation microtubule from cytoskeleton. metallopeptidase peptide deformylase. involved in the reduction of a trans-2,3 enoylacyl moiety to chain. a saturated Functionalpolypeptide plant chain ENR forms is astranded a single parallel domain homotetramer, consisting and of each a seven- by inhibiting enoyl (acylfatty carrier acid protein) synthase reductase (ENR). of the type-II methionine. because cytoplasmic proteinwith translation an in unformylated methionine eukaryotes residue.thesis However, initiates in protein chloroplast is syn- like that of prokaryotes. Actinonincauses treatment a rapid decrease in D1 proteinPSII synthesis and monomers, assembly into andultimately a leading subsequent toinvestigations decline stunting, have demonstrated bleaching in that actinonin and effectively photosynthesis, kills necrosis. a Recent } 38 L., (Fig. 1). Artemisia } 36 This article is a US Government work www.soci.org and is in the public domain in the USA Laurus nobilis D.C. and The phytotoxicity of 37 If this suggestion is verified, it 39,40 {(1R,2S,4S)-rel-1-methyl-4-(1-methy- The WSSA herbicide handbook lists but a study using physionomics and Xanthoxylum rhetsa 23 22 spp., Eucalyptus 24 spp., The herbicide cinmethylin The mode of action of cinmethylin (and 1,4-cineole) has eluded As mentioned above, inhibition of plant protein phosphatases Endothall (7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid), a These monoterpenes are phytotoxic. endothall’s mode ofcauses action inhibition of lipid as and protein unknown, synthesis, electrolyteand leakage but membrane dysfunction, mentions affects mRNA that synthesisas an and it uncoupler. may However, act it issame now molecular known target that site endothall as has cantharidin the as a herbicide. cineoles and several other monoterpenes appears to be associated with the presence of an epoxide ring. lethyl)-2-[(2-methylphenyl)methoxy]-7-oxabicyclo[2.2.1]heptane is a cineolebackbone of 1,4-cineole, herbicide with the addition of incorporating a benzylthat ether moiety the was added entire to monoterpene lower the volatility of the natural product. wileyonlinelibrary.com/journal/ps 4.1 Phytotoxins ofThe microbial origin success ofpathogens bialaphos and and glufosinatephytotoxins. soil indicates There microbes thatorganisms are plant are for many excellent newmolecular advantages sources chemical target sites. in of backbones The abilityof searching new that to toxins may produce such for sufficient agricultural affect amounts microbes use a good new system. by However, there large-scale are also fermentationMany some of limitations. makes these phytotoxins target enzymes thatlarge-scale may prohibit use their asReaders herbicides interested because in of thisarticle. mammalian topic toxicities. are referred to a recent review 4 NATURALNOT PRODUCTS CURRENTLY WITH AFFECTED TARGET BY SITES COMMERCIAL HERBICIDES scientists for a long time, Cinmethylin was in factbiorational developed synthetic program by to Shelltargeted the discover Chemical glycerol-3-phosphate shuttle. new A during phytotoxic insecticides dioxalane a intermediate that was identified.structures led to Optimization rigid bicyclic structures of withactivity. improved herbicidal the Some monocyclic ofbackbone of the the monoterpene cineoles bicyclic found in nature. structures possessed the basic metabolomics approaches suggests thatplant tyrosine aminotransferase. this herbicide inhibits spp.). One of the majoris 1,8-cineole constituents (1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane). of Another these plantnaturally essential oils occurring but{1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane less abundant cineole is 1,4-cineole 3.4 Cineole herbicide Cineoles are volatile symmetricalessential monoterpenes oils present of inSalvia the many aromatic plants (e.g. has broad consequencesinhibit on many plants. serine/threonine Cantharidinenzymes), and protein which endothall phosphatases makes (up evolutionunlikely. to of a 21 resistant target site very herbicide first commercialized in the 1950s, is a structuralof analogue cantharidin. Itin aquatic has environments. been used primarily for weed control would be the most recent discovery of a newtarget commercial herbicide site.

522 523 strains but the 53,54 2 Streptomyces 2 2 NH NH OH NH N NH O Tentoxin 2 O O N O O NH O The toxicological implications N 2 N N H O 55 NH 2 O OH O NH wileyonlinelibrary.com/journal/ps O O HO 2 N H NH O HN NH OH N N H HN Actinonin Ascaulitoxin agycone O O HO O Ribofuranosyl triazolone HO H N N N O 2 Syringomycin H H N O OH OH O NH HO O Cl O NH N H www.soci.org OH O OH HO O O O HN OH Ribofuranosyl triazolone (Fig. 2) is another natural phytotoxin O HN OH HO H N O of this molecular targetdevelopment. site may also have deterred herbicide that targets adenylosuccinate synthetaseof upon its phosphorylation primary hydroxyl. However, this molecule is readily obtained cost of synthesis appearedproherbicide to that be must prohibitive.in convey Hydantocidin bioactivity is order a via toinvolved phosphorylation in inhibit purine biosynthesis. adenylosuccinate synthetase, an enzyme irreversible inhibitor of ornithinepredominant carbamoyl form transferase of the and toxin the inherbicides infected have tissues. been No developed commercial to target this enzyme. 4.1.5 Hydantocidin andHydantocidin adenylosuccinate (Fig. synthetase 2) is produced by different and has beentime the seriously subject considered of as intense a research. natural It herbicide, was at one O HO O O O OH O Hydantocidin O Cyperine HO HN HO OH Macrocidin A OH Anhydro-D-glucitol O HO inplanta 2 + 2 NH OH This article is a US Government work NH and is in the public domain in the USA N H OH O - O O OH S 2 O O O 2 H N NH O - OH O O P NH Albucidin + O O N pathovars, the causal agent of H N N OH Cinnacidin NH N N H O N O N Thaxtomin A O O O 2 NN NH Ornithine carbamoyl transferase is a key Pyridazocidin N H NO N HO 52 2 Phaseolotoxin H N O 3 68: 519–528 H + 2012; Pseudomonas syringae Natural products of microbial origin with target sites not currently utilized by commercial herbicides. 50,51 Natural products for herbicide discovery enzyme in the urea cyclephosphate to that citrulline. converts Although ornithine phaseolotoxin is andhibitor a of carbamoyl ornithine reversible carbamoyl in- transferase, it is hydrolyzed by peptidases to produce octicidine. Octicidine, in contrast, is an Pest Manag Sci 4.1.4 Phaseolotoxin andPhaseolotoxin ornithine transcarboxylase (Fig. 2) isduced a by sulfodiaminophosphinyl peptide pro- halo blight on legumes. Itcarbamoyl transferase. is a competitive inhibitor of ornithine wide range of plants, including many agriculturallydifficult-to-control important weed and species. Actinonin provides anparadigm excellent for designing and synthesizingtargeting herbicidal peptide compounds deformylase,peptide especially deformylases leads to as resistance to actinonin, overexpression which might be of a useful approach to developing transgenicplants. herbicide-resistant Figure 2. Alternaria 68: 519–528 2012; 61 However, tentoxin 62 Upon post-emergence subunit of proton ATPase amino functionality of a 63 59 β ζ FE Dayan, DK Owens, SO Duke Pest Manag Sci Pseudomonas syringae, is one of the ) carrying an amino acid substitution which makes this particular target site 60 sp. strain (No. 620 061) that were isolated from that causes extreme chlorosis of the foliage of sensitive Upon phosphorylation, 2,5-anhydro-d-glucitol resembles Tentoxin inhibits the energy transfer of the chloroplast- lysine residue. Binding of thedolase interferes phosphorylated with the fungal normal catalytic toxin function of toHowever, this enzyme. al- this same phosphorylated fructosemammalian analog also aldolase, inhibits alternata species by inhibiting chloroplast development. questionable for a commercial herbicide. 4.1.8 Tentoxin andTentoxin chloroplast ATPase (Fig. 2) is a cyclic tetrapeptide produced by application, pyridazocidin led tofrom the 1–2 development of days symptoms afterHigh application application rates produced on necrosis, broadleaf whilerates lower and application grass induced weeds. emerging chlorosis, leaves. with Theto a symptoms what of particular pyridazocidin hasdiquat), impact were been and similar it on observed wasmechanism newly for proposed of that action. bipyridinium Bipyridinium the herbicidesI herbicides compound are (e.g. had electron photosystem- a acceptors similar superoxide that radical, reduce which molecularof ultimately oxygen other reactive to leads oxygenlipid form to species peroxidation. a that the When lead isolatedbipyridinium production to chloroplasts herbicides, rapid are the membrane treatedsuperoxide reduction with of radical molecular leadsoxygen, oxygen to known to as light-dependentthe the consumption Mehler Mehler of reaction, reaction.acts Pyridazocidin through further a induced establishing reversible reduction/oxidationto that mechanism photosynthetic linked the electron compound reported transport. natural Pyridazocidin product to is manifestthis type herbicidal the of activity mechanism. first through 4.1.10 Syringomycin andSyringomycin membrane perforation (Fig. 2), from many cyclic lipodepsinonapeptide microbiallarge phytotoxins. amphiphilic It is moleculehydrophobic a with 3-hydroxy fatty a acid tail. polarvarying This length peptide (from hydrophobic C10 tail head to isserine C14) and of and residue is a via bound toof an the nine N-terminal amide non-ribosomally synthesized bond. aminoacids. Syringomycin acids The bound is to chlorine composed fatty of syringomycin is important in imparting fructose-1,6-bisphosphate, but is lackinggroup the on anomeric carbon hydroxyl 2.mation This of hydroxyl group a is covalent required bond for the to for- the localized CF1 ATPase. Tentoxin-resistantChlamydomonas reinhardtii mutants (tobacco and on CF1 ATPase suggestrole that this in target site the plays mode a determining of action of tentoxin. also interferes with thepolyphenol transport oxidase into of the the plastidnot nuclear-coded affect of the enzyme transport-insensitive sensitive species. The plants, linked relationship butbetween does the effect of tentoxin on the this activity are the very abundanthexokinase glycolytic and glucosyltransferases, phosphorfructokinase. and polyphenol oxidase processing is not understood. 4.1.9 Pyridazocidin andPyridazocidin electron diversion from (Fig. PSI 2)Streptomyces was initiallya identified soil from sample cultures collected of in Honduras. The 58 56 , and was O This article is a US Government work www.soci.org activity. and is in the public domain in the USA NRRLB-24 108for O N H in vitro BOA chlorinus Subsequently, albucidin was Bacillus megatarium 57 OH O subsp. Citral Indeed, 2,5-anhydro-d-glucitol was Sarmentine N OH O Pelargonic acid O 59 O O N DIMBOA in some plant species, that induces chlorosis -glucitol and fructose-1,6-bisphosphate HO D 1 − O Streptomycesalbus Natural products of plant origin with target sites not currently It was noticed that it was a natural analog of fructose, and, 4.1.7 2,5-Anhydro- and bleaching. Albucidin has moderateactivity, with levels broadleaf of weeds pre-emergence beingPre-emergence more sensitive herbicidal than grasses. activityof implied that action the maybleaching, mechanism as involve the development metabolic ofwas the perturbation halted at majority the cotyledonary not of stage. affected Post-emergence activity limited plants broad was spectrum. However, to the onset ofslow symptoms and was seemed extremely to appearFrom preferentially its structure, in it new could be growth hypothesized tissues. thatmay its mode be of similar action toalbucidin that needs of to be hydantocidin. bioactivated It prior toaction. is exerting not its phytotoxic known whether isolatedfrom its phytotoxic activity using a bioassay-guided fractionation. wileyonlinelibrary.com/journal/ps examined for its antiviral effects. 4.1.6 Albucidin Albucidin (Fig. 2)derivative was of initially discovered oxetanocin as from a semi-synthetic by conventional syntheticsuitable means, starting backbone which for developing may new herbicides. make it a more Figure 3. utilized by commercial herbicides. bisphosphorylated when incubated with ain plant-cell-free the extract presence of ATP. The enzymes most likely responsible for compound is a very potent nucleoside toxin,less with than lethality 100 rates at g ha aldolase Bioactivation of fungal phytotoxins2,5-anhydro-d-glucitol is (Fig. not 2) is unusual. a For fungal metaboliteFusarium example, isolated from solani, NRRLgrowth but 18 did 883. not appear to This have a phytotoxin direct inhibited root based on theabove), prior it knowledge was reported postulatedanalog that on plants hydantocidin as would (see utilize a this fructose substrate.

524 525 - 79 + 80 In addition to having 73 82 They are broad-spectrum, foliar- wileyonlinelibrary.com/journal/ps 81 L.) have been used in traditional medicine A recent transcriptome approach to the effect These compounds have been patented as Therefore, it is likely that this plant possesses a 76 74 78 77 .). 75 et al for more information). www.soci.org 72 Some benzoxazinoids (e.g. BOA and DIMBOA) (Fig. 3) remain Both sarmentine and herbicidal fatty acids disrupt the plant Herbicidal fatty acids have a long history of use in weed control The herbicidal mode of action of benzoxazinoids is still some soil persistence, it was demonstrated thatproduct a soil of degradation BOAbenzoxazinoids. may account for most of the phytotoxicity of ATPase functions. numberofbioactivecompounds.Thebioassay-guidedpurification of the crude extract ofspectrum long contact pepper led natural to herbicide isolationbeen sarmentine. of patented the Sarmentine as broad- has a herbicide but it is not yet commercialized. herbicides, but nouse product to date. has been commercialized for such active in soils,potential and for their producing levels plant correlate species. with the allelopathic of benzoxazinoids on plants showedvery that broad these effects, compounds which had of made the action identification not of possibletreated their plants. on mode the basis of transcriptome profiles of 4.2.2 Sarmentine andSarmentine fatty acids (Fig. 3) is an exampleto of the herbicide ethnobotanical discovery approach frompepper natural (Piper products. longum The fruitsfor of the long treatmentby of Zaveri several diseases and ailments (reviewed The phytotoxicity of sarmentine andherbicidal its fatty analogs acids with matched similar that tails, of such as decenoic acid. 4.2 Phytotoxins ofIn plant origin addition toSections 3.2 the and 3.4 respectively, triketones there areof and several natural other products examples produced the by plants cineoles thatof may new serve mentioned chemistry as for a in source the discoverymodes of of new action. herbicides and/or new 4.2.1 Benzoxazoline (BOA) Benzoxazinoids are exudedroots in of their a number glucosylatedand of a form few grass by non-Poaceae speciesof species. the (e.g. The wheat, biological aglycones rye possess activitiesinsecticidal an and array activity, including maize) and fungicidal, mayBelz also antimicrobial play and a role in allelopathy (see cuticle, which leads to celldesiccation membrane damage and followed ultimate by tissue rapid postulatedthatthecommercialherbicidefattyacidpelargonicacid death. Additionally, it(Fig. has 3) also been causes light-independent inductionleakage, of cell likely membrane caused bymembrane, intercalation and a of resultant the light-driven peroxidase fatty activity acid which into the applications, and someused of as them natural have herbicides. been patented and are unknown, although a number ofthat these research compounds groups interfere have with reported bothATPase electron activity transport in and mitochondria as well as plasma membrane H applied, post-emergent herbicides that leadand to burndown. plant desiccation As withfatty sarmentine, acids the are herbicidal influencedwith activities by optimum of the activity lengthand against tobacco of achieved crabgrass, their with cucumber, C9–C11 aliphaticwith either velvetleaf tails, tails. shorter The or longer potency tails. decreases 67 L.). in vitro Lemna pauci- This article is a US Government work 68 and is in the public domain in the USA Cirsium arvense 71 sp. DA060097, a plant Its activity is associated has been patented as a 69 Nectria μM. An investigation of its mode 65 in vitro. Therefore, this toxin appears Syringomycin units can assemble into 64 Ascochyta caulina infecting Canada thistle ( 68: 519–528 lower than 1 50 I 2012; 70 with an Cinnacidin shares some structural features with jasmonic 66 Its mode of action may be similar to that of coronatine, although Ascaulitoxin aglycone inhibited the growth of The structures of two similar macrocidins (macrocidin A Natural products for herbicide discovery pathogen that causes cankers on manya tree cyclopentalenone species. It ring consists system of via linked an amide to bond. Initial an biological isoleucinesuggested characterization of promising subunit cinnacidin herbicidal activity. Symptomsinclude of stunting and cinnacidin chlorosis, which spread throughout thetissues. foliar it is more activeact on as cool-season a hormone-like grasses. herbicide by Like mimickingacid. coronatine, the role it of may jasmonic mycoherbicide for managing weeds. to have a novel mechanism ofinterconversion action or that amino may acid involve transporters. amino acid of action revealed thatbut it ultimately acts resulting in slowly,reversible chlorosis initially by supplemental and stopping addition death. growth bition of Its of most amino activity amino acid was because acids. the synthesis phytotoxic Inhi- in effect of not ascaulitoxin wasd-amino the also acids. reversed mechanism by A of metabolomic action, approachcaused distinct revealed changes that in amino the acids, toxin interferes suggesting with that the this activity toxin of aminotransferases. However,alanine neither aminotransferase nor alanine glyoxylate aminotransferase were inhibited by the toxin with the production ofprotein the phytotoxin amino ascaulitoxin acid andacid) aglycone its (Fig. 2). (2,4,7-triamino-5-hydroxyoctanoic non- 4.1.12 Macrocidins Macrocidins (macrocidin Aacids shown that were identified in in field Fig. isolates 2) ofPhoma the pathogenic macrostoma are fungus cyclic tetramic acid, and the twojasmonic may acid activity have is similar transientlonger and effects lasting. the The on activity exact plants, of molecular cinnacidin mechanismto although is be of elucidated. action remains Infected tissues exhibited bleaching and chlorotic symptoms, macromolecules that are insertedcreating within pores the cellular-membrane that arerapid necrosis freely in plant permeable tissues. to cations, leading to Pest Manag Sci and this toxin has been patented for herbicide use. 4.1.11 Cinnacidin The novel natural producta cinnacidin fungal (Fig. fermentation 2) extract was of isolated from its biological activity. costata and macrocidinwere B) subsequently tested were for herbicidalapplication activity. elucidated, Post-emergence of macrocidins and causedinhibition these similar on chlorosis broadleaf compounds andinfected weeds growth by to the thatsensitive. pathogen. observed Grass Although in weeds the thewith did tissues what observed not is symptoms appear typically to were observed be for consistent inhibitors of HPPD, 4.1.13 Ascaulitoxin aglycone The plant pathogen tests against this enzymeenzyme activity. 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The phenomology of citral action on 86,87 88 91 especially in light of the pressing need to 83 89 Many natural products may be good phytotoxins that have Why the herbicide industry has not put more of its resources into These characteristics make sarmentine and fatty acids good introduce herbicide classes withordertocombattheevolutionofherbicideresistance.Onepossible new mechanisms ofreason is action that in natural productsactivity, have and already attempts been to optimizedthem simplify for their less architecture active. often However,(e.g. render this triketone is herbicides). certainly As not discussed always by the Duke case in this issue, microtubules is distinct from that of well-knownused mitotic as inhibitors herbicides, such as oryzalin,novel suggesting that target it site may in have disrupting a mitosis. herbicide and is the activeoil-based ingredient of natural a number herbicides. of lemongrass wileyonlinelibrary.com/journal/ps there appears to be many factors hinderingintroduction the of development new and mechanisms of herbicidethese action, are based but on most economical of considerationsof rather than scientific on opportunities. lack modes of actions that differ fromherbicides those of the (Table current 2). commercial herbicides They because mayproduced their economically be and structures the poorly structuralto are modifications improve suited needed their too physicochemical to propertieslosses cause complex unacceptable use of to activity. as provide be However, sufficient proof the thatrelatively notable natural simple examples products structures mentioned canto that also can herbicide provide be discovery.for a natural Interestingly, successful herbicides there approach basedmicrobial toxins are on (Table 2), plant more in spite productsfar of patents the the than more fact abundant. that based the on latter are by semi-synthetic modification of natural products inefforts their discovery is unclear, This review providesafforded but by a natural glimpse products.throughput The of screening natural the process (a structuralon of high extended- diversity many potential numberopposed target of to sites the compounds human over(a approach tested long high of number high-throughput periods of screening compounds ofvery tested short time), on times) selected as enabled targetcompounds sites the in tailored selection of tothe specifically designed interact case with offrom specific natural herbicides, products, target allherbicides, namely sites. the the phosphinothricin, 7-oxa-bicycloheptanes In commercial the andnew triketone products chemical cineoles, classes introduced of derived compoundsaction. with unique mechanisms of 5 CONCLUSIONS 4.2.3 Citral andCitral microtubules (Fig. 3) isoils a that diterpene can component account oflemongrass for many (Cymbopogon up citratus plant to essential 80% of the steam distillate, as in may be causedbinding by complexes. the release of chlorophyll from its natural citral are needed for adequatecitral burndown disrupts microtubule of polymerization in weeds, the vapor of desiccants to aid in the harvesting of cropand plants. pelargonic Caprylic acid acid (C8) (C9) appear todesiccants be for the use most in efficient dry fatty bean acid species. within minutes of exposure.

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