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Duke, S.O. 1990. Natural pesticides from plants. p. 511-517. In: J. Janick and J.E. Simon (eds.), Advances in new crops. Timber Press, Portland, OR.

Natural Pesticides from Plants

Stephen O. Duke


  1. INTRODUCTION
  2. PLANT-DERIVED COMPOUNDS WITH PESTICIDAL POTENTIAL
    1. Herbicides
    2. Insecticides
    3. Fungicides
    4. Nematicides and Molluscicides
    5. Rodenticides
  3. FACTORS INFLUENCING DEVELOPMENT OF NATURAL PESTICIDES
    1. Discovery
    2. Development
  4. THE FUTURE
  5. REFERENCES
  6. Fig. 1
  7. Fig. 2
  8. Fig. 3
  9. Fig. 4

INTRODUCTION

Several pressures have accelerated the search for more environmentally and toxicologically safe and more selective and efficacious pesticides. Most commercially successful pesticides have been discovered by screening compounds synthesized in the laboratory for pesticidal properties. The average number of compounds that must be screened to discover a commercially viable pesticide has increased dramatically, so that new discovery strategies must be considered. Increased emphasis on reduced-tillage agriculture will make adequate control of weeds more dependent on chemical control. New herbicides will be needed to fully meet this challenge. The increasing incidence of pesticide resistance is also fueling the need for new pesticides. Furthermore, most synthetic chemicals that have been commercialized as herbicides are halogenated hydrocarbons with relatively long environmental half-lives and more suspect toxicological properties than most natural compounds. Thus, natural compounds have increasingly become the focus of those interested in discovery of pesticides.

Tens of thousands of secondary products of plants have been identified and there are estimates that hundreds of thousands of these compounds exist. There is growing evidence that most of these compounds are involved in the interaction of plants with other species-primarily the defense of the plant from plant pests. Thus, these secondary compounds represent a large reservoir of chemical structures with biological activity. This resource is largely untapped for use as pesticides. This review will provide an overview of those compounds from plants that have been utilized for pest control, examples of some compounds with pesticidal potential, and a discussion of considerations in development of natural plant compounds for pesticidal use.

PLANT-DERIVED COMPOUNDS WITH PESTICIDAL POTENTIAL

Herbicides

Inhibition of plant growth and production of phytotoxic symptoms by certain plants and their residues is a well established phenomenon. In searching for potential herbicides from plants, screening of compounds known to function in plant-plant interactions is a logical strategy. All plants produce secondary compounds that are phytotoxic to some degree. However, in only a relatively few cases has it been established that particular compounds provide the producing species a competitive advantage over other species that are less tolerant to the compound. Only a few of these allelochemicals have been actively pursued as herbicides and, in these cases, the natural compound has been modified. A derivative of the terpenoid allelochemical 1,8-cineole (Fig. 1), with the common name of cinmethylin (Fig. 1), is being commercially developed. Toxaphenereg., a mixture of chlorinated camphene derivatives, was sold as a herbicide and an insecticide, but was removed from the market in 1982 by the EPA. Other very weakly phytotoxic compounds from plants such as benzoic acids can be made much more herbicidally active by halogen substitutions. Several benzoic acid derivatives such as dicamba (3,6-dichloro-2-methoxybenzoic acid) are widely used as herbicides.

A few highly phytotoxic plant-produced compounds have been discovered. However, none have been developed as herbicides. The sesquiterpenoid lactone, artemisinin from Artemisia annua L., was found to inhibit plant growth as well as the commercial herbicide cinmethylin. Other compounds, such as 2,4-dihydroxy-1,4-benzoxazin-3-one are as active as plant growth inhibitors as many herbicides. Plants produce many photodynamic compounds, such as hypericin (Fig. 1), that are strongly phytotoxic, provided they can be introduced into the plant cell. These compounds are unlikely to be developed as pesticides because, in the presence of light, they are toxic to all living organisms. However, any plant can be caused to generate phytotoxic levels of photodynamic porphyrin compounds by treating the plant with both d-aminolevulinic acid (Fig. 1), a natural porphyrin precursor, and 2,2'-dipyridyl, a synthetic compound. This relatively safe combination of compounds is being developed as the "laser" herbicide. Several classes of commercial herbicides have recently been shown to act by causing target plant species to accumulate phytotoxic levels of protoporhyrin IX a photodynamic chlorophyll and heme precursor. Thus, a natural product, not the synthetic herbicides is the acutely toxic compound in these cases. Application of protoporhyrin IX alone to plant issues, however, is not effective, apparently because it does not reach the proper cellular compartment in sufficient quantity.

A problem with plant-produced phytotoxins as potential herbicides is that in the native state, they are generally only weakly active compared to commercial herbicides. Most known allelochemicals would have to be applied at rates of more than 10 kg/ha to achieve significant weed control whereas, most recently marketed herbicides would achieve the same level of control at levels three orders of magnitude smaller. This is not unexpected, because production of highly phytotoxic compounds would lead to strong autotoxicity unless the producing plant develops metabolic or physical mechanisms to cope with its own phytotoxins. Some of the more potent allelochemicals are toxic to the producing species and this autotoxicity has been implicated in vegetation shifts. Microbial conversion of relatively non-phytotoxic compounds in the soil to highly phytotoxic derivatives has been documented.

Plants have been much more successfully exploited as sources of pesticides for pests other than weeds. This is probably due to several factors. The selection pressure caused by pathogens and herbivores has probably been more acute and intense than that caused by plant competitors. A plant species can effectively compete with plant foes in many ways other than by poisoning them and having to cope with autotoxicity. Pathogens and herbivores have many potential physiological and biochemical sites of action for pesticides that the plant does not share. Biosynthesis of a compound to affect one of these sites reduces the chance of autotoxicity. Thus, the chemical option is generally a more attractive option in responding to a herbivore or pathogen that can rapidly devour or invade the plant than it is in responding to a plant competitor.

Insecticides

Throughout history, plant products have been successfully exploited as insecticides, insect repellents, and insect antifeedants. Probably the most successful use of a plant product as an insecticide is that of the pyrethroids. The insecticidal properties of the several Chrysanthemum species were known for centuries in Asia. Even today, powders of the dried flowers of these plants are sold as insecticides. After elucidation of the chemical structures of the six terpenoid esters (pyrethrins) responsible for the insecticidal activity of these plants, many synthetic analogs have been patented and marketed. Synthetic pyrethroids have better photostability and are generally more active than their natural counterparts.

Another plant terpenoid, camphene (Fig. 2), was a very successful herbicide in its polyhalogenated form. Sold as Toxaphrenereg., this product was the leading insecticide in the United States before it was removed from the market. Although this product was a mixture of over two hundred chlorinated forms of camphene, certain specific compounds in the mixture were found to be much more active than the mixture on a unit weight basis. Many other terpenoids have been demonstrated to have insecticidal or other insect-inhibiting activities. For instance, azadirachtin and other terpenoids of the limonoid group from the families Meliaceae and Rutaceae are potent growth inhibitors of several insect species.

Nicotine (Fig. 2) and nornicotine, components of several members of the genus Nicotiana, have been used commercially as insecticides. N. rustica is the chief commercial source. Other natural analogues of nicotine have been shown to have significant insecticidal properties and one, anabasine or neonicotine (Fig. 2), has been produced as an insecticide from the shrub, Anabasis aphylla, in the Soviet Union. Synthetic variations of nicotine such as 5'-methylnornicotine have been demonstrated to be effective insecticides. Ryanodine, an alkaloid from the tropical shrub, Ryania speciosa, has been used as a commercial insecticide against European corn borer. Physostigmine, an alkaloid from Physostigma venenosum was the compound upon which carbamate insecticides were designed. Furo-quinoline and beta-carboline alkaloids such as dictamine and harmaline, respectively, are potent photosensitizing compounds that are highly toxic to insect larvae in sun light. The relative high cost toxicity to mammals, and limited efficacy have limited the use of natural alkaloid insecticides.

Preparations of roots from the genera Derris, Lonchocarpus, and Tephrosia, containing rotenone (Fig. 2), were commercial insecticides in the 1930s. Rotenone is a flavonoid derivative that strongly inhibits mitochondrial respiration. No other phenolic compound has been used commercially as an insecticide, although the content of certain phenolic compounds in plant tissues have been correlated with host plant resistance to insects and many have been demonstrated to be strong insect growth inhibitors and antifeedants.

As in plants, delta-aminolevulinic acid (ALA), in combination with 2,2'-dipyridyl, can cause accumulation of toxic levels of photodynamic porphyrin compounds. Larvae of several insect species, when fed these compounds and exposed to light were rapidly killed. Protoporphyrin IX the same compound caused to accumulate in plants by certain photobleaching herbicides, is the prophyrin responsible for the toxicity of these compounds to insects. Other photodynamic compounds from plants such as polyacetylenes are acutely toxic to insects, however, their general toxicity would probably preclude them from commercial use.

Control of insects can be achieved by means other than causing rapid death. Plants produce many compounds that are insect repellents or act to alter insect feeding behavior, growth and development ecdysis (molting), and behavior during mating and oviposition. Most insect repellents are volatile terpenoids such as terpenen-4-ol. Other terpenoids can act as attractants. In some cases, the same terpenoid can repel certain undesirable insects while attracting more beneficial insects. For instance, geraniol will repel houseflies while attracting honey bees. Compounds from many different chemical classes have been reported to act as insect antifeedants. Thus, polygodial a sesquiterpenoid from Polygonum hydropiper, is a potent inhibitor of aphid feeding. Several plant-derived steroids that are close analogues of the insect molting hormone, ecdysterone, prevent insect molting. Other chemically unrelated terpenoids inhibit molting by unknown mechanisms. Plant terpenoids that act as locomotor excitants, biting or piercing suppressants, ovipositioning deterrents, or mating behavior disruptants have been described. More than a dozen plant-produced terpenoid juvenile hormone mimics have been found to effectively sterilize insects. Plants contain a myriad of compounds with potential for commercial development in controlling insects.

Fungicides

Without an immune system to combat pathogenic microorganisms, plants rely primarily on chemical protection with secondary compounds. Compounds that inhibit the establishment of and growth of plant pathogens are termed phytoalexins. Many of these secondary compounds have been chemically characterized and proof is developing that these compounds have such a role in plant disease prevention and control. In fact, there is some evidence that certain synthetic fungicides used in plant protection act by inducing the production of phytoalexins in plants.

Several plant-derived compounds have been demonstrated to be strong elicitors of phytoalexins. For instance, certain oligosaccharide components of cell walls from stressed or dying higher plant cells will act as elicitors. Further knowledge of plant-derived phytoalexin elicitors could lead to their use as fungicides. Several isoflavonoid compounds, such as glyceollin, phaseolin, and pisatin (Fig. 3) in soybean, garden bean, and pea, respectively have been implicated in protection of these crops from pathogens. Many other confirmed or suspected phytoalexins have been identified. Some of these compounds have demonstrated utility against fungi under field conditions. Foliar application of the phenolic lactone juglone (Fig. 3), a product of several walnut species, provides better protection of bean seedlings from rust than some commercial fungicides. Terpenoid phytoalexins) and fungicides are known and some have been tested for commercial efficacy. Wyerone, an acetylenic acid derivative produced by legumes as a phytoalexin has a wide fungicidal spectrum against plant pathogens and has been successfully tested against fungal infection of crop plants. Despite a repertoire of many antifungal and antibacterial compounds, plant products have not been used to any significant extent in the development of antimicrobial pesticides.

Nematicides and Molluscicides

Many plant species are known to be highly resistant to nematodes. The most well-documented of these include marigolds (Tagetes spp.), rattlebox (Crotalaria spectabilis), chrysanthemums (Chrysanthemum spp.), castor bean (Ricinus communis), margosa (Azardiracta indica), and many members of the family Asteraceae (family Compositae). The active principle(s) for this nematicidal activity has not been discovered in all of these examples and no plant-derived products are sold commercially for control of nematodes. In the case of the Asteraceae, the photodynamic compound alpha-terthienyl (Fig. 3) has been shown to account for the strong nematicidal activity of the roots.

The plant-derived saponins are generally highly toxic to snails. Cyanogenic glucosides are responsible for resistance of certain legumes to snails and slugs. No plant-derived natural products are commercial products are available for control of snails and slugs.

Rodenticides

Plants produce a myriad of compounds that are poisonous to mammals. Some of these, such as strychnine (Fig. 3), are used in commercial rodenticides. The chronic poison warfarin and several analogues are coumarin derivatives, This chemistry led to discovery of indanediones and 4-hydroxy-2H-1-benzopyran-2-ones as rodenticides.

FACTORS INFLUENCING DEVELOPMENT OF NATURAL PESTICIDES

Discovery

The secondary compounds of plants are a vast repository of compounds with a wide range of biological activities. This diversity is largely the result of coevolution of hundreds of thousands of plant species with each other and with an even greater number of species of microorganisms and animals. Thus, unlike compounds synthesized in the laboratory, secondary compounds from plants are virtually guaranteed to have biological activity and that activity is highly likely to function in protecting the producing plant from a pathogen, herbivore, or competitor. Thus, a knowledge of the pests to which the producing plant is resistant may provide useful leads in predicting what pests may be controlled by compounds from a particular species. This approach has led to the discovery of several commercial pesticides such as the pyrethroid insecticides. Isolation and chemical characterization of the active compounds from plants with strong biological activities can be a major effort compared to synthesizing a new synthetic compound. However, the assurance of biological activity and improvement in methods of purification and structural identification is shifting the odds in favor of natural compounds.

Considering the probability of plant secondary products being involved in plant-pest interactions, the strategy of randomly isolating, identifying, and bioassaying these compounds may also be an effective method of pesticide discovery. Biologically active compounds from plants will often have activity against organisms with which the producing plant does not have to cope. Many secondary compounds described in the natural product, pharmacological and chemical ecology literature have not been screened for pesticidal activity. This is due, in part, to the very small amounts of these compounds that have been available for screening.

The discovery process for natural pesticides is more complicated than that for synthetic pesticides (Fig. 4). Traditionally, new pesticides have been discovered by synthesis, bioassay, and evaluation If the compound is sufficiently promising, quantitative structure-activity relationship-based synthesis of analogues is used to optimize desirable pesticidal properties. The discovery process with natural compounds is complicated by several factors.

First, the amount of purification initially conducted is a variable for which there is no general rule. Furthermore, secondary compounds are generally isolated in relatively small amounts compared to the amounts of synthesized chemicals available for screening for pesticide activity. Therefore, bioassays requiring very small amounts of material will be helpful in screening natural products from plants. A number of published methods for assaying small amounts of compounds for pesticidal and biological activities are available in the allelochemical and natural product literature. At some point in the discovery process, structural identification is a requirement. This step can be quite difficult for some natural products. Finally, synthesis of the compound and analogues must be considered. This is generally much more difficult than identification. Despite these difficulties, modern instrumental analysis and improved methods are reducing the difficulty, cost and time involved in each of the above steps.

Development

Few pesticides that are found to be highly efficacious in testing are ever brought to market. Many factors must be considered in the decision to develop and market a pesticide. An early consideration is the patentability of the compound. A patent search must be done for natural compounds as with any synthetic compound. Prior publication of the pesticidal properties of a compound could cause patent problems. Compared to synthetic compounds, there is a plethora of published information on the biological activity of natural products. For this reason, patenting synthetic analogues with no mention of the natural source of the chemical family might be safer than patenting the natural product in some situations.

The toxicological and environmental properties of the compound must be considered. Simply because a compound is a natural product does not insure that it is safe. The most toxic mammalian poisons known are natural products and many of these are plant products. Introduction of levels of toxic natural compounds into the environment that would never be found in nature could cause adverse effects. However, evidence is strong that natural products generally have a much shorter half-life in the environment than synthetic pesticides. In fact, the relatively short environmental persistence of natural products may be a problem, because most pesticides must have some residual activity in order to be effective. As with pyrethroids, chemical modification can increase persistence.

After promising biological activity is discovered, extraction of larger amounts of the compound for more extensive bioassays can be considered. Also, analogues of the compound should be made by chemical alteration of the compound and/or chemical synthesis. Structural manipulation could lead to improvement of activity, toxicological properties, altered environmental effects, or discovery of an active compound that can be economically synthesized. This has been the case with several natural compounds that have been used as a template for commercial pesticides (e.g., pyrethroids).

Before a decision is made to produce a natural pesticide for commercial use, the most cost-effective means of production must be found. Although this is a crucial question in considering the development of any pesticide, it is even more complex and critical with natural products. Historically, preparations of crude natural product mixtures have been used as pesticides. However, the potential problems in clearing a complex mixture of many biologically active compounds for use by the public may be prohibitive in today's regulatory climate. Thus, the question that will most probably be considered is whether the pure compound will be produced by biosynthesis and purification or by traditional chemical synthesis.

Before considering any other factors, there are two advantages to the pesticide industry to industrial synthesis. They have invested heavily in personnel and facilities for this approach. Changing this approach may be difficult for personnel trained in disciplines geared to use it. Secondly, in addition to the patent for use, patents for chemical synthesis often further protect the investment that a company makes in development of a pesticide.

However, many natural products are so complex that the cost of chemical synthesis would be prohibitive. Even so, more economically synthesized analogues with adequate or even superior biological activity may tip the balance toward industrial synthesis. If not biosynthesis must be considered. There are a growing number of biosynthetic options.

The simplest method is to extract the compound from field-grown plants. To optimize production, the species and the variety of that species that produce the highest levels of the compound must be selected and grown under conditions that will optimize their biosynthetic capacity to produce the compound. Genetically manipulating the producing plants by classical or biotechnological methods could also increase production of some secondary products. For instance, low doses of diphenyl ether herbicides can cause massive increases in phytoalexins in a variety of crop species.

Another alternative is to produce the compound in tissue or cell culture. With these methods, cell lines that produce higher levels of the compound can be rapidly selected. However, genetic stability of such traits has been a problem in cell culture production of secondary products. Cells that produce and accumulate massive amounts of possibly autotoxic secondary compounds are obviously at a metabolic disadvantage and are thus selected against under many cell or tissue culture conditions. A technique, such as an immobilized cell column that continuously removes secondary products can increase production by decreasing feedback inhibition of synthesis, reducing autotoxicity, and possibly increasing generic stability. Other culture methods that optimize production can also be utilized. For instance, supplying inexpensively synthesized metabolic precursors can greatly enhance biosynthesis of many secondary products. Also, plant growth regulators, elicitors, and metabolic blockers can be used to increase production.

Genetic engineering and biotechnology may allow for the production of plant-derived secondary products by gene transfer to microorganisms and production by fermentation. This concept is attractive because of the existing fermentation technology for production of secondary products. However, it may be prohibitively difficult for complex secondary products in which several genes control the conversion of several complex intermediates to the desired product.

Genetic engineering might also be used to insert the genetic information for production of plant-produced pesticides from one plant species to another species to be protected from pests. However, such transgenic manipulation of the complex metabolism of a higher plant might be extremely difficult. A simpler alternative might be to infect plant-colonizing microbes with the desired genetic machinery to produce the natural pesticide, as has been done with bacterial-produced insecticides.

THE FUTURE

Plants contain a virtually untapped reservoir of pesticides that can be used directly or as templates for synthetic pesticides. Numerous factors have increased the interest of the pesticide industry and the pesticide market in this source of natural products as pesticides. These include diminishing returns with traditional pesticide discovery methods, increased environmental and toxicological concerns with synthetic pesticides, and the high level of reliance of modern agriculture on pesticides. Despite the relatively small amount of previous effort in development of plant-derived compounds as pesticides, they have made a large impact in the area of insecticides. Minor successes can be found as herbicides, nematicides, rodenticides, fungicides, and molluscicides. The number of options that must be considered in discovery and development of a natural product as a pesticide is larger than for a synthetic pesticide. Furthermore, the molecular complexity limited environmental stability, and low activity of many biocides from plants, compared to synthetic pesticides, are discouraging. However, advances in chemical and biotechnology are increasing the speed and ease with which man can discover and develop secondary compounds of plants as pesticides. These advances, combined with increasing need and environmental pressure, are greatly increasing the interest in plant products as pesticides.

REFERENCES


Fig. 1. Some plant-produced compounds and derivatives with herbicidal activity. I-1,8-cineole, II-cinmethylin, III-hypericin, IV-delta-aminolevulinic acid.


Fig. 2. Some plant-produced compounds with insecticidal activity. I-camphene, II-nicotine, III-anabasine, IV-rotenone.


Fig. 3. Some plant-produced compounds with fungicidal nematicidal and rodenticidal activity. I-pisatin II-juglone, III-alpha-terthienyl, IV-strychnine.


Fig. 4. Pesticide discovery strategies for synthetic versus natural products.


Last update September 5, 1997 aw