Professional Documents
Culture Documents
3.09.1 Introduction
The direct use of natural products as pesticides or as leads for pesticides has been reviewed previously.14 This short
review will highlight methods and strategies and the rationale behind the use of natural products as insecticides with
a more detailed discussion of new promising leads, including a few examples from the authors research.
The use of botanical insecticides dates back two millennia. The use of plant products in Europe goes back to
more than 150 years ago, until the discovery of synthetic insecticides (organochlorines, organophosphates,
carbamates, pyrethroids), which replaced the botanical insecticides. Overuse of these synthetic insecticides has
led to problems such as acute and chronic pollution, negative effects on wildlife (fish, birds), disruption of
biological control and pollination, groundwater contamination, and resistance to pesticides.5,6
237
238 Natural Product-Based Biopesticides for Insect Control
Despite the concerted effort being made to breed or engineer plants with increased resistance to pests and
disease, there will always be a need for crop protection, partly for mass-produced crops and partly for niche
areas such as horticulture, greenhouses, organic farming, households, and gardens where biopesticides are
particularly prevalent. There is a need for environmentally friendly and consumer-friendly products that also
preferably exhibit novel modes of action to mitigate resistance problems.
The development of crop protectants is similar to drug development and is presently based on synthesizing
novel molecules that interact with well-defined targets found in the pest. The difference with drug develop-
ment is that the compounds will be used on a large scale and must be free of all environmental toxicity. Also the
products should be relatively stable and should be safe for human use (e.g., nontoxic, rapid breakdown).
Toxicity is the major hurdle that needs to be overcome in the development of novel pesticides. Most
compounds are eliminated due to adverse toxic effects. Screening nontoxic plants for activity reduces the
risk of discovering toxic biopesticides. The chance of finding novel biopesticides is increased by screening
plants that are used for food, cosmetics, or spices, or plants that have traditionally been used as crop protectants.
Plants have an excellent track record in providing novel leads for crop protection, particularly in the field of
insecticides. This can be attributed to the evolution of secondary metabolites for host plant protection against
insects, pathogens, and plant competitors. Our ancestors were quite successful in exploring and exploiting this
natural treasure. The documented use of plant extracts and powdered plant parts as insecticides goes back at
least as far as the Roman Empire. There are reports of the use of pyrethrum (Tanacetum cinerariaefolium,
Asteraceae) as early as 400 BC. The first pure botanical insecticide used as such dates back to the seventeenth
century when it was shown that nicotine obtained from tobacco leaves was lethal to plum beetles. Around 1850,
a new plant insecticide known as rotenone was introduced. Rotenone is a flavonoid derivative extracted from
the roots of two different Derris spp. (Fabaceae) and Lonchocarpus spp. (Fabaceae). The ground seeds of
Sabadilla, a plant of South American origin known as Schoenocaulon officinale (Liliaceae), are one of the plant
insecticides exhibiting the least toxicity to mammals.7
Currently, there are a number of botanical insecticides that are being marketed worldwide. Some examples
are neem (Azadirachta indica), rotenone, and ryania, which is obtained from the roots and stems of a native South
American plant known as Ryania speciosa (Flacourtiaceae). The active compounds isolated from the botanical
pesticides may also eventually provide basic structures contributing to the development of new pesticides.
Recent reviews have been published in this connection.14,6,8
The main markets for botanical pesticides are organic agriculture, horticulture, green houses, parks, gardens, and
households. Organic agriculture is a market with a high demand for biopesticides, as organic growers cannot use
conventional agrochemicals. This market is currently expanding owing to consumers demand for improved food
safety and the environmental problems associated with the use of synthetic pesticides. With an annual average growth
of 30%, organic farming in the EU is one of the most dynamic agricultural sectors. Many more farmers have come
onboard since the enactment of Community Legislation regulating organic production (Council Regulation 2092/91/
EEC of 24 June 1991). One of the overarching objectives of the Common Agricultural Policy (CAP) is the achievement
of sustainable agricultural production in Europe, which requires environmentally friendly pest control measures.
Botanical pesticides also feature the advantage of being compatible with other low-risk options that are
acceptable for insect management, which include, inter alia, the use of pheromones, oils, detergents, entomo-
pathogenic fungi, predators, and parasitoids. This significantly increases the likelihood of botanical pesticides
being integrated into integrated pest management (IPM) programs.
New products need to be developed to meet the demands of this growing market, and to this end a systematic
approach to finding new plant-derived products needs to be developed. Different sources can be considered,
such as traditionally used plants, readily available plants, or agricultural waste products. Extracts from these
plants need to be screened for activity and then isolated and active molecules identified. Cultivation methods
then need to be developed in the case of plants exhibiting interesting activity. Environmentally friendly
extraction methods should be applied to achieve the final products. The successful development of biocides
from discarded citrus peels in the United States is an excellent example of how such an approach can work.
However, only a handful of botanical insecticides are in use today on commercially significant vegetable and
fruit crops. In this chapter, plant products currently in use will not be reviewed (recent reviews on this topic can
be found in Copping and Duke1 and Isman6), but rather new sources and trends for future use and potential
commercialization will be discussed.
Natural Product-Based Biopesticides for Insect Control 239
3.09.2.2 Azadirachtin/Dihydroazadirachtin
Azadirachtin is extracted from the neem tree (A. indica A. Juss). The tree is an attractive broad-leaved evergreen,
which is thought to have originated in Burma. It is now grown in the more arid subtropical and tropical zones of
Southeast Asia, Africa, the Americas, Australia, and the South Pacific Islands. The neem tree provides many useful
compounds used as pesticides. The most significant neem limonoids are azadirachtin, salanin, meliantriol, and
nimbin.9 Products containing azadirachtin can be used in a wide range of crops, including vegetables (such as
tomatoes, cabbage, and potatoes), cotton, tea, tobacco, coffee, protected crops and ornamentals, and in forestry.
Azadirachtin has several effects on phytophagous insects and is thought to disrupt insect molting by antagonizing the
effects of ecdysteroids. This effect is independent of feeding inhibition, which is another observed effect of the
compound.1,10 The antifeedant/repellent effects are dramatic, with many insects avoiding treated crops, although
other chemicals in the seed extract, such as salanin, have been shown to be responsible for these effects. Azadirachtin
is sold by a large number of different companies as an emulsifiable concentrate (EC) under a wide range of trade
names. Azadirachtin-based products are widely used in India and are increasingly popular in North America, where
they have found a place for garden use and in organic growing. Azadirachtin is considered to be nontoxic to mammals
and is not expected to have any adverse effects on nontarget organisms or on the environment.1,11,12
Dihydroazadirachtin is a reduced form of the naturally occurring azadirachtin obtained from the seed
kernels of the neem tree. It is effective against a wide range of insect pests. The two compounds are functionally
identical in their antipupation properties. Dihydroazadirachtin has both antifeedant and insect growth regulator
(IGR) properties. Products based on dihydroazadirachtin are not widely used outside the Indian subcontinent,
although it is registered as a technical powder and an end-use product for indoor and outdoor use in the United
States. Dihydroazadirachtin exhibits low toxicity to mammals, and risk to the environment is not expected
because, under approved use conditions, it is not persistent, is relatively short-lived in the environment, and is
metabolized by ubiquitous microorganisms in the soil and aquatic environments.1
The toxicological data for neem-based preparations show that the nonaqueous extracts appear to be the most
toxic, the unprocessed materials, seed oil and the aqueous extracts being less toxic. For all preparations, a
reversible effect on the reproductive capacity of both male and female mammals seems to be the most important
toxic effect subsequent to subacute or chronic exposure.13 This is the reason why an array of azadirachtin- and
neem extract-based insecticides and pesticides are available on the market today.
240 Natural Product-Based Biopesticides for Insect Control
3.09.2.3 Karanjin
Karanjin is extracted from Derris indica (Lam.) Bennet (synonym Pongamia pinnata (L.) Pierre). Karanjin is a
potent deterrent to many different genera of insects and mites in a wide range of crops. Karanjin has a dramatic
antifeedant/repellent effect, with many insects avoiding treated crops. It suppresses the effects of ecdysteroids
and thereby acts as an IGR and antifeedant. There are claims that it inhibits cytochrome P-450 in susceptible
insects and mites. Karanjin has not achieved wide acceptance as an insecticide. There is no evidence of allergic
or other adverse effects, and it is not expected that karanjin-based products will have any adverse effects on
nontarget organisms or on the environment.1
3.09.2.4 Nicotine
Nicotine is the main bioactive component of the tobacco plants Nicotiana tabacum L., N. glauca Graham, and,
particularly, the species N. rustica L. It is also present in a number of other plants belonging to the families
Lycopodiaceae, Crassulaceae, Leguminosae, Chenopodiaceae, and Compositae. The average nicotine content
of the leaves of N. tabacum and N. rustica is 26% dry weight. It is used for the control of a wide range of insects,
including aphids, thrips, and whitefly, on protected ornamentals and field-grown crops, including orchard fruit,
vines, vegetables, and ornamentals.
It was once prepared from the extracts of the tobacco plant but is now often obtained from waste of the
tobacco industry, or it is synthesized. Nicotine is a nonsystemic insecticide14 that binds to the cholinergic
acetylcholine nicotinic receptor (nAch) in the nerve cells of insects, leading to a continuous firing of this
neuroreceptor.15 Nicotine has been used for many years as a fumigant for the control of many sucking insects.
Nicotine is very toxic to humans by inhalation and by skin contact. It is toxic to birds, fish, and other aquatic
organisms, and is toxic to bees, but has a repellent effect. In the United Kingdom, nicotine is subject to
regulation under the Poisons Act. The use of nicotine as a pesticide is banned in South Africa, severely
Natural Product-Based Biopesticides for Insect Control 241
restricted in Hungary, canceled in Australia and New Zealand, as well as not being registered in numerous
African, Asian, and European countries.1
They are nonsystemic insecticides with contact action. Initial effects include paralysis, with death occurring
later. They have some acaricidal activity.18 They are approved for use in organic production. Pyrethrins have
moderate mammalian toxicity, and there is no evidence that the addition of synergists increases this toxicity.
The compounds show low toxicity to birds, but are highly toxic to fish and honeybees (although they exhibit a
repellent effect on bees).1
3.09.2.9 Rotenone
Rotenone, also known as derris root, tuba root, and aker tuba (for the plant extract) and barbasco, cube, haiari,
nekoe, and timbo (for the plants), is obtained from Derris, Lonchocarpus, and Tephrosia species, which were used
originally in Asia and South America as fish poisons. The four major active ingredients are rotenone, deguelin,
rotenolone, and tephrosin acting as inhibitors of NADH-ubiquinone oxidoreductase activity depending on the
overall molecular configuration and the E-ring substituents.19 Rotenone is used to control a wide range of
arthropod pests. It is an inhibitor of site I respiration within the electron transport chain of susceptible insects
and is a selective, nonsystemic insecticide with contact and stomach action and secondary acaricidal activity.20
Rotenone has been cleared for use in organic farming when insect pressure is very high. Rotenone has a high
mammalian toxicity, with the estimated lethal dose for humans being 300500 mg kg1. It is more toxic when
inhaled than when ingested and is very toxic to pigs. It is not toxic to bees, but combinations with pyrethrum are
very toxic. It is very toxic to fish and must not be used near water courses.1
used economically only to treat infested crops, and it has no systemic activity. The rapidity of its effect is an
advantage in the control of boring insects. More recently, a new class of insecticides has been discovered that
provides exceptional control through action on a novel target, the ryanodine receptor, for example,
Rynaxypyr, anthranilic diamides, and substituted phthalic acid diamides with potent insecticidal activity.
These substances activate ryanodine-sensitive intracellular calcium release channels in insects.2224 Ryania
extracts are moderately toxic to mammals, but very toxic to fish.
3.09.2.11 Sabadilla
Sabadilla is an insecticidal preparation from the crushed seeds of the liliaceous plant S. officinale Gray (formerly
Veratrum sabadilla Retr.), which was used by native people of South and Central America as an insecticide for
many years. Sabadilla has been used commercially since the 1970s. The seeds of S. officinale contain a mixture of
alkaloids (veratrine) consisting of an approximately 2:1 mixture of cevadine and veratridine, in combination
with many minor components, all of which are esters of the alkamine veracine. The product is produced by
grinding the seeds of the plant and subsequent concentration. The seeds contain between 2 and 4% alkaloids.
Cevadine, veratridine, and related ceveratrum alkaloids have a mode of action that is similar to that of the
pyrethrins, in that they activate the voltage-sensitive sodium channels of nerve, heart, and skeletal muscle cell
membranes, although the binding site appears to be different from that of the pyrethroids.
They are nonsystemic insecticides with contact action. Initial effects include paralysis, with death occurring
later.1 Sabadilla powder is not used widely in crop protection, but it is approved for use in organic farming
systems. This powder has a low mammalian toxicity, but it is an irritant to mucous membranes. Sabadilla
powder is not active against beneficial insects and may be used in insect control strategies that use them.25
is potentially effective against insect pests that are resistant to chemical-based insecticides. It is nontoxic to
humans and beneficial insects and/or natural predators. The main component of YE-621 is starch syrup mainly
from corn and potatoes.1,26
3.09.3.2 Monoterpenes
Monoterpenes are the main components of plant EOs and, like these oils, have also been tested for their
insecticidal effects. Some mosquito repellents include p-menthane-3,8-diol from mint as the active ingredient,
and citronellal is also used in mosquito coils. A number of veterinary products for flea and tick control on
Natural Product-Based Biopesticides for Insect Control 245
Achillea biebersteinii, Sitophilus granarius, Tribolium confusum Fumigant toxicity Calmasur et al.115
A. wilhelmsii
Acorus gramineus Lycoriella ingenua Toxic Park et al.116
Allium sativum Lycoriella ingenua Toxic Park et al.117
Alpinia calcarata Callosobruchus maculatus Fumigant toxicity Abeywickrama
and repellent et al.118
Apium graveolens Aedes aegypti Adulticidal Chaiyasit et al.119
Armoracia rusticana Lycoriella ingenua Toxic Park et al.117
Artemisia annua Tribolium castaneum Fumigant toxicity, Goel et al.120
repellent
A. herba-alba, Bemisia tabaci, Aphis gossypii, Thrips tabaci Toxic Soliman
A. monosperma et al.121,122
A. sieberi Callosobruchus maculatus, Sitophilus oryzae, Fumigant toxicity Negahban et al.123
Tribolium castaneum
A. vulgaris Thrips palmi Repellent Yi et al.124
Tribolium castaneum Fumigant toxicity Wang et al.125
A. princeps Sitophillus oryzae, Bruchus rugimanus Fumigant toxicity Liu et al.126
A. nilagirica Aedes aegypti, Anopheles stephensi, Culex Larvicidal Verma et al.127
quinquefasciatus
Carum carvi Lycoriella ingenua Fumigant toxicity Park et al.128
Aedes aegypti Adulticidal Chaiyasit et al.119
Chamaecyparis Aedes aegypti, A. albopictus Larvicidal Kuo et al.129
formosensis
Chenopodium Lycoriella ingenua Toxic Park et al.116
ambrosioides
Chloroxylon swietenia Helicoverpa armigera Antifeedant Kiran et al.130
Anopheles gambiae, Culex quinquefasciatus, Fumigant toxicity
Aedes aegypti
Spodoptera litura Toxic Kiran et al.131
Cinnamomun cassia Chrysomya megacephara Ovicidal Shen et al.132
C. camphora Resseliella oculiperda Repellent Van Tol et al.133
Sitophillus oryzae, Bruchus rugimanus Liu et al.126
C. zeylanicum Musca domestica Knock down and Samarasekera
mortality et al.134
Citrus reticulate Lycoriella ingenua Toxic Park et al.128
Convallaria majalis Ixodes ricinus Repellent Thorsell et al.135
Coriandrum sativum Thrips palmi Fumigant toxicity Yi et al.124
Croton nepetaefolius Aedes aegypti Larvicidal Morais et al.136
C. argyrophyloides
C. sonderianus
C. zenhtneri
Cryptomeria japonica Aedes aegypti, A. albopictus Larvicidal Cheng et al.137
Lepisma saccharina Repellent and Wang et al.138
insecticide
Cuminum cyminum Lycoriella ingenua Toxic Park et al.128
Tribolium castaneum Fumigant toxicity Chaubey et al.139
Cupressus Aedes aegypt Adulticidal Chaiyasit et al.119
sempervirens
Thrips palmi Fumigant toxicity Yi et al.124
Curcuma zedoaria Aedes aegypti Adulticidal Chaiyasit et al.118
C. longa Wild mosquitoes, anthropophilic black flies Repellent Tawatsin et al.140
Cymbopogon citratus Lycoriella ingenua Toxic Park et al.128
Musca domestica Knock down and Samarasekera
mortality et al.134
C. martini Callosobruchus chinensis, Tribolium castaneum Repellent Kumar et al.141
C. schoenanthus Callosobruchus maculatus Toxic Ketoh et al.142
C. nardus Musca domestica Knock down and Samarasekera
mortality et al.134
(Continued )
246 Natural Product-Based Biopesticides for Insect Control
Table 1 (Continued)
(Continued )
Natural Product-Based Biopesticides for Insect Control 247
Table 1 (Continued)
domestic pets contain d-limonene from citrus peels as the active ingredient. Another important use of
EO components is for the fumigation of beehives to control the honeybee parasite varroa (Varroa Jacobson
and V. destructor) and the tracheal mite (Acarapis woodi). Thymol4245 and menthol46,47 are used to control
these mites. Other monoterpenes have also been tested: linalyl acetate, (R)-myrtenyl acetate, (S)-perillyl
acetate, although thymyl acetate exhibited high toxicity against V. destructor and significantly lower
toxicity against A. mellifera.48 Camphor and eucalyptol are also used for this purpose.47 Several mono-
terpenoids exhibit toxicity against stored product and urban pests, are good spatial repellents, and could
be used in pest control.49
Table 2 provides an overview of the latest publications on insecticidal monoterpenes for the period
200608 (in part). Most of these compounds are known structures and have been studied as part of broader
EO research.
3.09.3.3 Sesquiterpenes
Sesquiterpenes feature a different set of characteristics, which also have an influence on insect activity, most
effectively as contact irritants.49 Many species of the Celastraceae family such as the Chinese bittersweet
(Celastrus angulatus) are widely distributed and used as traditional insecticides in China. These plants contain
dihydro--agarofuran sesquiterpenoids based on a tricyclic 5,11-epoxy-5,10-eudesman-4(14)-ene skeleton.
The compact tricyclic scaffold seems to be a prerequisite for antifeedant or insecticidal activity as are the
substitutions at C-1, C-6, and C-8. Nicotinic diacid substituent may also be involved in the antifeedant activity,
possibly through neuronal action of nicotinic diacid.50 An emulsifiable mixture of celangulins has been
developed for insect control.51 This functions as a digestive poison acting on the midgut tissue of the target
insect larvae. Celangulins have structure-dependent effects on insect voltage-gated sodium channels52 and
inhibit carboxylesterase activity.
Natural Product-Based Biopesticides for Insect Control 249
Naturally occurring sesquiterpenoid dialdehydes of the drimane series such as polygodial, warburganal, and
muzigadial isolated from Polygonum and Warburgia spp. (Polygonaceae) have been thoroughly researched owing
to their strong antifeedant activities and considerable attention has been devoted to the synthesis of these
compounds.53 The reactivity of the unsaturated dialdehyde functionality toward biological nucleophiles is
considered to account for the antifeedant activity of these substances.53 The antifeedant activity of polygodial
acetal derivatives (propylene and ethylene) is consistent with the proposed adduct formation with amino
groups.54 However, the lack of correlation between reactivity toward nucleophiles and the antifeedant effects of
250 Natural Product-Based Biopesticides for Insect Control
polygodial and warburganal suggests that their insect antifeedant action may depend on other properties as
indicated by the activity of ketoaldehydes and 3-hydroxydrimanes.55
The silphinenes are tricyclic sesquiterpenes isolated from Senecio palmensis (Asteraceae) that have antifeedant
and toxic effects on insects and structural similarity to the known GABA antagonist picrotoxinin. C-5, C-11,
and C-5-substituted silphinenes were active antifeedants against several insect (Spodoptera littoralis, Leptinotarsa
decemlineata) and aphid species. All insects tested responded to at least one silphinene analog and/or GABA
modulator (picrotoxinin/thymol), suggesting a shared GABA-mediated taste regulation mode of action for
these species.56,57 Furthermore, it has recently been shown that silphinenes interact with the GABA receptor of
Drosophila melanogaster larvae in a manner different from pycrotoxinin (PTX), and that rdl resistance (resistant
via an altered GABA receptor) in the field may have little effect on silphinene efficacy.58
Mixtures that include both monoterpenes (acting as a good spatial repellent) and sesquiterpenes (good
contact repellent) are extremely effective via both modes of action and show potential for residual repellent
action from a natural product.49
Table 3 shows the latest publications on insecticidal sesquiterpenes. The number of compound hits is
similar to that of monoterpenes; however, new structures are described and these are mostly antifeedants in
contrast to the monoterpenes shown in Table 2, which are all known and mostly toxic (fumigants). Therefore,
sesquiterpenes can be considered as an interesting source of molecular models with potentially useful insect
antifeedant properties.
(Continued )
Natural Product-Based Biopesticides for Insect Control 251
Table 3 (Continued)
3.09.3.4 Diterpenes
Clerodane diterpenoids have been found in hundreds of plant species from a number of different families. Several
genera from the Verbenaceae and Lamiaceae families have been identified as rich sources of neoclerodane
diterpenoids. These metabolites have attracted considerable attention for their biological activity, which includes
piscicidal, trypanocidal, and antibacterial properties. The insect antifeedant property of clerodane diterpenes is the
most extensively studied bioactivity of these compounds.59 Scutellaria and Ajuga genera (Lamiaceae) produce some
of the most potent clerodane antifeedants. In Scutellaria, jodrellin B (occurring in S. albida, S. galericulata, S. grossa,
S. polyodon, and S. woronowii) and scutecyprol B (found in S. columnae, S. cypria, S. grossa, and S. rubicunda) exhibit the
highest antifeedant index against S. littoralis.60,61 From Ajuga pseudoiva leaves, 14,15-dihydro-ajugapitin displayed
the highest activity.62 Furthermore, the genus Teucrium is one of the richest sources of clerodane diterpenes.63
252 Natural Product-Based Biopesticides for Insect Control
Ryanodane diterpenes are compounds that are structurally related to the known insecticide ryanodine
(see Section 3.09.2.10). Several ryanodane diterpenes, including ryanodol, cinnzeylanol, cinnzeylanone, and
cinnzeylanine, have been isolated from the Macaronesian paleoendemism Persea indica (Lauraceae).64,65
Ryanodol and didehydroryanodol, in contrast to ryanodine and didehydroryanodine, have low toxicity to
mice and limited activity at the mammalian ryanodine receptor but are potent knockdown agents for injected
houseflies or cockroaches, suggesting a possible difference in the target sites of mammals and insects.66 The
antifeedant activity of these compounds has been evaluated, showing the importance of the 11-hemiketal group
for the antifeedant effects of ryanodane diterpenes. The comparative antifeedant effects of several nonalkaloidal
and alkaloidal ryanoids supported the hypothesis of a ryanodol-specific mode of action in insects.64,67 The
insect-selective insecticidal and antifeedant effects of ryanodanes hold a promising future for their use as
biopesticides. However, their availability is a problem that would need to be addressed prior to potential
exploitation (Table 4).
3.09.3.5 Triterpenes
Quassinoids, the bitter compounds of the Simaroubaceae family, are a group of structurally complex and highly
oxygenated degraded triterpenes. They are divided into five groups according to their basic skeleton: C-18,
C-19, C-20, C-22, and C-25. In recent years, attention has been focused on quassinoids because several of them
have shown promising biological activities. Some quassinoids present insecticidal and antifeedant effects in
insects. Quassin was first used as an insecticide at the end of the seventeenth century, with the application of
Natural Product-Based Biopesticides for Insect Control 253
plant extracts from Quassia amara. More recent studies also reveal this activity in other species and/or other
quassinoids.68
Saponins are widely distributed among plants and have a wide range of biological properties. Cestrum parqui
(Solanaceae) is a shrub from Chile, and toxicity comes from the saponic fraction of the plant. Cestrum parqui
saponins, for example, are toxic to Schistocerca gregaria, S. littoralis, and Tribolium confusum. This toxicity may also
be the result of interference with ecdysone metabolism by interfering with dietary cholesterol.69,70 Alfalfa
saponins exhibited deterrent and toxic effects against the pea aphid Acyrthosiphon pisum.71 The larvicidal effect of
aqueous extracts of the African plants Hemidesmus indicus roots, Gymnema sylvestre, and Eclipta prostrata on Culex
quinquefasciatus larvae has been attributed to their high saponin content.72 Insecticidal soyasaponins have been
isolated from field pea (Pisum sativum) extracts.73 The total saponins from the roots and shoots of three Medicago
species (M. arabica, M. hybrida, and M. murex) included in the diet of L. decemlineata larvae reduced their feeding
and growth and survival rates.74
254 Natural Product-Based Biopesticides for Insect Control
The search for limonoids started way back when scientists started looking for the factor responsible for bitterness
in citrus, which has a negative impact on citrus fruit and the juice industry worldwide. The term limonoids was
derived from limonin, the first tetranortriterpenoid obtained from citrus bitter principles. Compounds from this
group exhibit a range of biological activities (insecticidal, antifeedant, and growth regulating) on insects as well as
antibacterial, antifungal, antimalarial, anticancer, and other activities. Although hundreds of limonoids have been
isolated from several different plants, their occurrence in the plant kingdom is exclusively confined to plant families
of the Rutales order, most abundant in Meliaceae and Rutaceae and less frequent in Cneoraceae and Harrisonia sp. of
Simaroubaceae. Limonoids are highly oxygenated modified triterpenoids with a prototypical structure derived
from a precursor with a 4,4,8-trimethyl-17-furanylsteroid skeleton. All naturally occurring citrus limonoids contain
a furan ring attached to the D ring at C-17 as well as oxygenated functional groups at C-3, C-4, C-7, C-16, and C-17.
There are fewer structural variations in limonoids found in Rutaceae as compared with Meliaceae, and these are
generally limited to the modification of A and B rings. The limonoids of Meliaceae are more complex with a very
high degree of oxidation and rearrangement in structure.9
Other triterpene classes and derivatives, including lanostanes, friedelanes, and cyloartanes, also exhibit
insect growth regulation effects7578 and therefore merit further investigation. Table 5 shows the reported
insecticidal triterpenes for the period 200608.
3.09.3.6 Alkaloids
Alkaloids research contributes to our understanding of their ecological role and provides essential information
on the structural requirements accounting for their insecticidal activity. While the direct use of these substances
Natural Product-Based Biopesticides for Insect Control 255
has recently diminished, they continue to serve as leads for synthetic analogues and are also indispensable
biochemical tools in mode-of-action studies. However, the development of novel insecticides of commercial
importance based on these prototypes is not readily predictable. Alkaloids are typically produced as a cocktail
of metabolically related compounds and occasionally co-occur with other nonalkaloidal substances, all mod-
ulating the toxicological properties of an individual component. Consequently, it would be fair to assume that a
single natural compound is not optimized for a particular biological activity. Progress in the research on natural
insecticides, botanicals in particular, has been surveyed from time to time.7,79,80 Specifically, Ujvary15 has
reviewed tobacco, lobeline, quinolizidine, unsaturated amides, veratrum, solanum, physostigmine (eserine),
ryanodine, Aconitum and Delphinium alkaloids, rocaglamide, cocaine, methylxanthines, isoquinoline-type alka-
loids, dioncophyllines, Erythrina, Stemona, Tripterygium, and Haplophyton alkaloids, and polyhydroxy alkaloids,
covering their insecticidal mode of action. Here, a few insights into insecticidal alkaloids are given.
Table 6 shows the latest reports on insecticidal alkaloids. Most of these publications are related to
previously known compounds except for harmaline81 whose insecticidal effects are described for the first time.
Dihydroagarofuran sesquiterpene esters and alkaloids are the main compounds exhibiting insect antifeedant
and insecticidal activities that have already been isolated from the species of Celastraceae. Insecticidal proper-
ties of Tripterygium wilfordii roots have been cited in the literature since 1931, and the sesquiterpene pyridine
alkaloids wilforine and wilfordine were identified as its active components.82 Several macrolide pyridine
alkaloids have recently been isolated from Euonymus spp. and Maytenus spp. (Celastraceae). The number and
orientation of the ester groups and the existence of pyridine alkaloids have a pronounced impact on the
insecticidal activity of these dihydro--agarofuran sesquiterpene polyol alkaloids.50,83 Accordingly, the struc-
ture of the nicotinic diacid and the components of the dihydro--agarofuran skeleton may affect the antifeedant
potency of these macrolide alkaloids and could be involved in the potential neuronal action of the nicotinic
diacid.
256 Natural Product-Based Biopesticides for Insect Control
Diterpenoid alkaloids are well-known compounds of pharmacological interest. Aconitine, the major and one
of the most toxic C-19 norditerpene alkaloids isolated from Aconitum napellus, and methyllycaconitine, the
principal toxic alkaloid of many Delphinium spp. but not found in Aconitum species, are among the most toxic
ones.15 The insecticidal effects of C-19 diterpene alkaloids and their effects on insect nicotine acetylcholine
receptors (nAChR) were already known. Recent studies on the antifeedant effects of C-19 norditerpenoid
(NDAs) and C-20 diterpenoid (DAs) alkaloids isolated from Aconitum, Delphinium, and Consolida
(Ranunculaceae) species showed that NDAs are better insect antifeedants and postingestive toxicants than
Natural Product-Based Biopesticides for Insect Control 257
the related DAs. Their antifeedant or insecticidal potencies did not coincide with their reported nAChR-
binding activity but did correlate with the agonist/antagonist insecticidal/antifeedant model proposed for
nicotinic insecticides. Among the most potent antifeedants are the NDAs 1,14-diacetylcardiopetaline,
18-hydroxy-14-O-methylgadesine, and 14-O-acetyldelectinine and the DA 19-oxodihydroatisine.84
Table 6 shows the latest publications on the topic for the period 200608 (April).
Lignans and biogenetically related secondary metabolites derived from phenylpropanoid precursors play a
significant role in protecting plants from insects. They mostly act as regulators of insect feeding, but in a few
cases they can also exert an influence on the specific physiological functions of insects. The mode of action of
such compounds is mostly unknown. One possible mechanism might be interaction with and disruption of the
endocrine system, which is crucial for the proper development of insects and is dependent on the action of
molting hormones (ecdysteroids).88 These compounds also affect feeding, excretion, and Trypanosoma cruzi
interactions with Rhodnius prolixus.89 A structureactivity study revealed that natural lignan lactones with
methoxy and/or methylenedioxy substituents showed significant activity that is strong enough to affect
plantinsect interactions. The presence of polar substituents, especially hydroxyl or glycosyl groups, often
reduces the activity. Nonpolar substituents such as methoxy or methylenedioxy groups enhance the activity not
only in lignans but also in simple phenylpropanoids.90
Coumarins are scantly studied insecticides and there is potential to exploit this chemically simple group of
natural products.91 Iridoids are known to deter feeding or decrease the growth rate of many generalist insect
herbivores. For example, catalpol-affected T. castaneum growth probably related to the inhibitory activity of this
iridioid against DNA polymerase.92 Phenylpropanoid derivatives accumulate in plants in response to insect
herbivory and therefore are antiherbivore substances.93 Tables 7 and 8 show the latest reports on the
insecticidal effects of the above mentioned type of compounds.
Table 7 Flavonoids, lignans, chromones, coumarins, etc. for the period 200608 (in part)
Precocene II Chromene Archips podana Modification of the insect sensory system Triseleva215
Isovitexin-29-O--[6-O-E-p- Flavonoid Helicoverpa armigera Antifertility Caasi-Lit et al.216
coumaroylglucopyranoside]
()-Homopterocarpin Isoflavonoid Spodoptera litura Antifeedants Morimoto et al.185
()-Methoxyhomopterocarpin pterocarpans Reticulitermes speratus
Quercetin glycoside, tannins Flavonoid, tannins Spodoptera frugiperda Insecticidal IGR Gallo et al.217
Kaempherol glycosides Flavonoid Sitophilus oryzae Insecticidal Taylor et al.218
Tanetin (6-hydroxykaempferol 3,7,49- Flavone Spodoptera littoralis Antifeedant Susurluk et al.189
trimethyl ether), 6-hydroxykaempferol
3,6-dimethyl ether
Rutin Flavone Anticarsia gemmatalis Antinutritional Hoffmann-Campo
et al.219
()-Kusunokinin Lignane Anticarsia gemmatalis Toxic Messiano et al.220
Yangambin Lignane Chrysomya megacephala Inhibition of postembryonic development, De Oliveira-Cabral
morphological alteration, and et al.221
oviposition reduction
Geniposidic acid, 10-Hydroxyloganin, Iridoid Kalotermes flavicollis, Toxicity Tzakou et al.222
deacetyldaphylloside, monotropein Crematogaster scutellaris
Khellin, visnagin, ammiol Chromone Spodoptera littoralis Antifeedant Sayed et al.223
2-Methyl-5,6,7-trimethoxychromone Chromone Spodoptera litura Antifeedant Morimoto and Komai224
Coumarin Coumarin Rhyzopertha dominica, Insecticidal Moreira et al.225
Sitophilus zeamais,
Oryzaephilus surinamensis
Murraxocin Coumarin Plecoptera reflexa, Clostera Toxic Sharma et al.91
cupreata, Crypsiptya
coclesalis
6-Hydroxy-7-isoprenyloxycoumarin, Coumarin Spodoptera frugiperda Antifeedant, toxic, IGR Vera et al.226
6-Methoxy-7-isoprenyloxycoumarin,
6,7-Methylenedioxycoumarin, 5-methoxy-
6,7-methylenedioxycoumarin,
6-Methoxy-7-(2-hydroxyethoxy)coumarin
Scopoletin Coumarin Spodoptera littoralis Antifeedant Susurluk et al.189
Emodin Anthraquinone Anopheles gambiae Larvicidal, Georges et al.227
Bemisia tabaci toxic
Table 8 Aromatic derivatives and organosulfur compounds for the period 200608 (in part)
Aromatic derivatives,
organosulfur compounds Type Target insect Action Reference
The main problem faced in the exploitation of natural compounds of plant origin as biopesticides is to ensure
their sustainable supply at low cost. Biopesticides and botanicals tend to be more expensive than synthetics, and
260 Natural Product-Based Biopesticides for Insect Control
some are not produced in great quantity or are no longer commercially available (e.g., nicotine). Several sources
of plant material may be used for botanical pesticide extraction. The simplest route is extraction from plants
harvested from wild plant resources. However, wild plant resources may be limited and hence may not permit
sustainable production. Moreover, some plants containing these compounds are endangered species due to
overexploitation.
An alternative is plant cultivation using conventional agricultural methods. Traditional cultivation
permits the sustainable production of plant material in the amount required for biopesticide production
and the ongoing improvement of production levels through breeding and selection of superior genotypes.
The investment and the long periods of time required to establish plantations as well as environmental
factors such as adverse weather conditions, pests, and diseases are the main disadvantages. It may also be
that plants with interesting activities only grow in certain regions and are difficult to cultivate outside of
their local ecosystems.94 Additionally, some interesting compounds accumulate in specialized tissues, such
as pyrethrins in flower heads of chrysanthemum, resulting in high labor costs related to harvest and
extraction.95
For plant species with interesting activity, sustainable and reproducible cultivation methods should be
developed as a clear alternative to traditional agriculture or wild plant collection. In the last few decades, great
progress has been made in plant cell cultivation for the production of botanical insecticides.95,96 Plant cell
culture is not affected by changes in environmental conditions and the plant material can be maintained
indefinitely in a defined production system. Despite considerable efforts, there are still problems in large-scale
production by means of plant cell cultures due to low yields, cell line instability, and low economical viability.
As an alternative to plant cell cultures, the use of organ cultures such as fast-growing hairy roots obtained
after transformation with Agrobacterium rhizogenes offers new opportunities for a sustainable in vitro production of
specific metabolites when the main location of metabolite biosynthesis is in the roots. These cultures are
genetically stable for long periods of time in contrast to what has been observed in many plant cell cultures and
can produce metabolites at levels comparable with those of intact plants. Recent developments in bioreactor
systems indicate that the industrial exploitation of this hairy root technology may be possible.9799 Studies on
the production of some commercially important botanical insecticides by means of hairy root cultures have
been carried out. Some examples are azadirachtin (A. indica100), tiophenes (Tagetes patula101), phytoecdysteroids
(Ajuga reptans var. atropurpurea,102 Ajuga turkestanica103), and nicotine (N. rustica104).
Additionally, this biotechnological method can be used as a source for the discovery of new pesticides in
roots of rare and endangered species that would otherwise be inaccessible. For example, we have investigated
Salvia broussonetii, a Canarian endangered endemic species that produces triterpenes in the aerial parts.105,106
The phytochemical study of these roots permitted the isolation of diterpenes such as the dehydroabietane
derivative 14-deoxycoleon U, which proved to be a potent antifeedant against L. decemlineata, and demethyl-
cryptojaponol, which was also toxic to this insect. Additionally, the diterpenes isolated from this root culture
showed strong selective cytotoxicity to insect Sf 9 cells.107
Aeroponically grown plants in controlled environments can also be a sustainable source of metabolites
from roots and aerial parts.108 This artificial system allows the control of the root nutrient and water
regimes, and also offers full access to the roots throughout the life of the plant. At the present time,
aeroponic culture provides opportunity for biomass production on a commercial scale and is being applied
to the production of medicinal crops.109 As part of our ongoing studies on the sustainable production of
natural biopesticides from endemic species, an aeroponic system for P. indica has been developed. The
aerial part and stems of this species are characterized by their content of insecticidal ryanodane- and
isoryanodane-type diterpenes.64,65,110 Aeroponic culture of this protected tree in a controlled environment
allowed investigation of the production of ryanodanes in aerial parts and roots. S. palmensis, an endemic
Canarian species found on the islands of Tenerife and La Palma, is also being cultivated. The aerial part
contains mostly silphinene-type tricyclic sesquiterpenes.56,57,64,110 We have adapted this species to aero-
ponic culture and in vitro culture of transformed roots with A. rhizogenes, and silphinenes were produced in
aerial parts and roots using both culture systems.
Natural Product-Based Biopesticides for Insect Control 261
The demand for nature-based biopesticides is rising steadily in all parts of the world. This is because of
increased public awareness of the environment, and the pollution potential and health hazards related to many
conventional pesticides. Extensive and systematic research has enhanced the effectiveness of biopesticides.
Also, the techniques for their mass production, storage, transport, and application have improved in recent
years.
Biopesticides are safer than conventional pesticides, which often are hazardous chemicals. They offer much
more activity targeted to the desired pests as opposed to conventional pesticides, which often affect a broad
spectrum of pests as well as birds and mammalian species. Often they are effective in very small quantities,
thereby offering lower exposure. They decompose quickly. Lastly, they can supplement conventional pesti-
cides when used in IPM programs. Such programs offer high crop yields while dramatically reducing
conventional pesticide use.
Globally, the biopesticides market is worth E158 million. The European market has doubled in size in
recent years, but the EU can only meet 45% of the demand for biopesticides. As consumers ask for greener
alternatives, and as organophosphates are phased out, older pesticide licenses are not being renewed. This is
creating a growing market for biopesticides.
Market trends:
The synthetic pesticides market is expected to show a declining trend at the rate of 1.5% per annum. At the
same time, the biopesticide market is growing and expected to reach more than a billion dollars in the next 5
years.
Key developments expected in the coming years are more R&D in biopesticides, an increase in genetically
modified crops, the application of IPM concepts, and a widening of organic farming.
Biopesticides today represent about 2.5% of the overall pesticides market, and are expected to grow to about
4.2% by 2010.
Orchard crops hold the largest share of biopesticides use at 55%.
However, the major constraint could be the changing and demanding regulations governing their registration
and release.111 Progress is being made toward achieving harmonization of requirements; however, the differ-
ences in detail required, and in the interpretation of the data, may undermine these efforts and continue to raise
the hurdles against the development of new biopesticides.
3.09.6 Conclusions
The main barriers to the commercialization of botanical insecticides are sustainability of the resource,
standardization of chemically complex extracts, and regulatory approval. Additionally, finding new natural
insecticides is not easy or is not currently being granted financial support as can be concluded from the lower
number of publications on natural products with insecticidal properties (and mostly known ones) for the period
200608 (April) in contrast to the large number of publications on insecticidal EOs.
Plant EOs and/or their components have a broad spectrum of activity against insect and mite pests, plant
pathogenic and other fungi, and nematodes. As such, they have considerable potential as crop protectants and
for pest management in other situations (e.g., urban pest control). Current information indicates that they are
safe to the user and the environment with few exceptions. However, the EOs that are most effective against
pests are often the most phytotoxic. The latter property requires serious attention when formulating products.
Moreover, selectivity among invertebrates is not well documented.
Among new natural products with promising insecticidal properties, it is believed that, in addition to
limonoids, attention should focus on the -dihydroagarofuran sesquiterpenes and related pyridine alkaloids,
silphinene-type sesquiterpenes, drimanes, ryanodane diterpenes (more so than their pyrrole derivatives),
lignans, flavonoids, and phenylpropanoids, among others. However, new single compound-based natural
insecticides are difficult to produce because compound isolation and identification takes time and effort, the
alternative being the production of standardized extracts once the active compounds are identified. New
extraction methods to produce standardized enriched extracts and biotechnological/traditional cultivation
methods are needed to produce new botanical biopesticides with commercial potential.
Like other alternative pest management products, EO-based pesticides and enriched standardized extracts
will not be a panacea for crop protection, but there should be substantial market niches, particularly certified
organic farming and urban pest control.
Regulatory approval in industrial nations is costly and time consuming. However, there is a growing demand
for organic production of food, and the number of pest management products that can be used in this
production is limited and it is here that botanical biopesticides can play an important role partially meeting
such demand.
Abbreviations
CAP Common Agricultural Policy
DA diterpenoid
EC emulsifiable concentrate
EO essential oil
EPA Environmental Protection Agency
GR granular formulation
Natural Product-Based Biopesticides for Insect Control 263
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Natural Product-Based Biopesticides for Insect Control 267
Biographical Sketches
Matas Reina Artiles received his Ph.D. in Chemistry in 1979 at the University of La Laguna,
Tenerife, under the supervision of Professor A. G. Gonzalez and Professor Dr. G. de la
Fuente. He was an assistant professor in Organic Chemistry for the period 197476. He
became Titulado Superior de Investigacion, CSIC at the Instituto de Productos Naturales y
268 Natural Product-Based Biopesticides for Insect Control
Agrobiologa in 1976. In 1985, he spent one and a half years as a postdoctoral researcher at the
University Rene Descartes in Paris, with Professor D. Mansuy. He began his independent
career at the CSIC in 1991, and currently he is Investigador Titular OPIS at the Instituto de
Productos Naturales y Agrobiologa. His research interests range from the chemistry of
alkaloids to biomimetic transformations of natural products.
Carmen Elisa Diaz completed her Ph.D. in Pharmacy in 1986 at the University of La Laguna
in Tenerife, under the supervision of Professor Braulio M. Fraga. In 1987, she obtained a
CSIC postdoctoral fellowship and became Cientfico Titular at the Instituto de Productos
Naturales y Agrobiologa, CSIC in 1988. She then spent 1 year as a postdoctoral researcher
with Professor B. V. Charlwoods group at Kings College University of London in 1989,
before joining the Chemistry and Biotechnology of Natural Productss group at the Instituto
de Productos Naturales y Agrobiologa, CSIC.
Braulio M. Fraga was born in Tenerife (1944) and received his Ph.D. in Chemistry at the
University of La Laguna (1970), where he lectured in Organic Chemistry for several years. In
1971, he was honored with the Young Researcher Award from the Spanish Royal Society of
Chemistry. He obtained a permanent position in the Spanish Council for Scientific Research
as a Tenured Scientist in 1972 and was later appointed Research Scientist (1986) and
Research Professor (1987). He was director of the Institute of Natural Products (Tenerife)
from 1988 to 1991 and has been the representative of the Spanish Council for Scientific
Research in the Canary Islands since 1991. He had previously been appointed Professor of
Organic Chemistry at the University of Valencia (1981). His research interests range from
chemistry to biotransformation of natural products, especially in the field of terpenes. He has
authored more than 180 scientific publications.