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benzoate: a novel avermectin derivative for control of lepidopterous pests

R. K. Jansson, R. Brown, B. Cartwright, D. Cox, D. M. Dunbar, R. A. Dybas,1 C. Eckel, J. A. Lasota, P. K. Mookerjee, J. A. Norton, R. F. Peterson, V. R. Starner and S. White

Merck Research Laboratories, Agricultural Research and Development, Merck & Co., Inc., P.O. Box 450, Hillsborough Road Three Bridges, NJ 08887 U.S.A. 1Current Address: 298 Reaville Rd., Flemington, NJ 08822

Abstract Emamectin benzoate (MK-0244) is a novel semi-synthetic derivative of the natural product in the avermectin family of 16-membered macrocylic lactones. This epi-methyl amino derivative has unprecedented potency against a broad spectrum of lepidopterous pests with LC90values ranging between 0.001Ð0.02 ug/ml in ingestion-based foliar spray assays. Emamectin benzoate is ca. 1,500-fold more potent against certain armyworm species, and 2- to 5-fold more potent against diamondback moth, Plutella xylostella (L.), than abamectin. It is 18- to 80,400-fold more potent against P. xylostella, cabbage looper, Trichoplusia ni (Hubner), and beet armyworm, Spodoptera exigua (Hubner), than other new , such as , chlorfenapyr, and tebufenozide. In the field, the compound is very effective at controlling all lepidopterous pests of cole crops at low use rates (8.4 g ai/ha). The mode of action is similar to abamectin (GABA - and glutamate-gated chloride channel agonist) and is not cross resistant with any other compound currently used commercially. The first registrations for the compound on cole crops in the U.S. and Japan are anticipated for 1997. An overview of its potential for control of lepidopterous pests in cole crops is provided.

Key words: Emamectin benzoate, avermectin derivative, lepidoptera, cole crops

Introduction Although abamectin was potent against mites and Avermectins are a family of 16-membered macrocyclic a select number of insects, it was considerably less lactone natural product homologues produced by the potent against most Lepidoptera. This spectrum soil microorganisms, Streptomyces avermitilis MA- deficiency prompted a focused, medicinal chemistry 4680 (NRRL 8165) and were isolated at Merck and biological testing program that resulted in the Research Laboratories from a soil sample collected in discovery of 4"-epi-methylamino-4"-deoxyavermectin Japan by researchers at the Kitasato Institute (see B1 (emamectin) in 1984 (Figure 1). MK-0243 (the Campbell, 1989 and references therein). Isolation of hydrochloride salt of emamectin), which was derived the crude fermentation product of S. avermitilis yielded from abamectin via a five-step synthesis (Cvetovich a complex of eight closely related avermectin et al., 1994), was discovered after screening several homologues (A1a, A1b, A2a, A2b, B1a, B1b, B2a, and hundred avermectin derivatives in an in vivo screen B2b), of which avermectins B1 (a and b) were the major using tobacco budworm, Heliothis virescens (Guenee), components. Abamectin, the non proprietary name and southern armyworm. Spodoptera eridania ≥ assigned to avermectin B1, is a mixture of B1a ( 80%) (Cramer) (Dybas and Babu, 1988; Dybas et al., 1989; ≤ and B1b ( 20%). This mixture was very potent against Mrozik, 1994; Mrozik et al., 1989). The benzoate salt mites and certain insect species (Dybas et al., 1989). of emamectin (coded MK-0244) had improved thermal Abamectin was developed for crop protection and is stability and greater water solubility compared with currently sold commercially for control of mites and the hydrochloride salt. MK-0244 was assigned the certain insect pests on several ornamental and nonproprietary name emamectin benzoate and is horticultural crops in over 50 countries. , a currently being developed as a crop protection 22, 23 dihydro semi-synthetic derivative of abamectin, ; first registrations in the U.S. and Japan was developed widely for control of ecto- and are anticipated for 1997. The present paper presents endoparasites of food and companion animals as well an overview of the potential of emamectin benzoate as for control of the causative agent of river blindness, for control of lepidopterous pests of cruciferous crops. Onchocerca volvulus, in man (see Campbell, 1989; Lariviere et al., 1985). Mode of action The mode of action of the avermectins has been reviewed by several authors (Arena, 1994; Fisher and Mrozik, 1984; Rohrer and Arena, 1995; Turner and

Chemical control 171 O H OCH3 - + CÐO H3ON 4" OCH H 3 O H3C O 4" CH 23 3 CH3 H 22 O O H3C 15 O 25 13 17 26 O R 19 25 CH3 11 H 10 O O 9 OH 1 H 8 2 3 7 4 O 5 CH3 H OH

a: R25 = H b: R25 =

Figure 1. Structure of emamectin benzoate (MKÐ0244)

Schaeffer, 1989). All studies suggested that there are pests range between 0.002Ð0.89 ug/ml (Dybas, 1989; few qualitative differences in the mode of action of Cox et al., 1995b; Jansson and Dybas, 1996) (Table the avermectin compounds studied, including 1). Emamectin hydrochloride was up to 1,500-fold emamectin benzoate; thus, it is believed that most, if more potent against armyworm species, e.g. beet not all, avermectins have a similar mode of action. armyworm, Spodoptera exigua (Hubner), than The properties of the avermectins are abamectin (Dybas et al., 1989; Mrozik et al., 1989; due predominantly to potentiation and/or direct Trumble et al., 1987). Emamectin hydrochloride was opening of glutamate-gated chloride channels, whereas also 1,720-,884-, and 268-fold more potent to S. in insects, it is likely that avermectins bind to multiple eridania than methomyl, thiodicarb, and fenvalerate, sites (including glutamate and GABA) in insect respectively, and 105- and 43-fold more toxic to cotton chloride channels. In general, the chloride ion flux bollworm, Helicoverpa zea (Boddie), and tobacco produced by the opening of the channel into neuronal budworm, H. virescens, larvae than abamectin (Dybas cells results in loss of cell function and disruption of and Babu, 1988). Recent studies showed that nerve impluses. Consequently, invertebrates are emamectin benzoate was 875- to 2,975-fold and 250- paralyzed irreversibly and stop feeding. Maximum to 1,300- fold more potent that tebufenozide to H. mortality of is achieved within 4 days. virescens and S. exigua, respectively. Emamectin Although the avermectins do not exhibit rapid knock benzoate was also 12.5- to 20-fold and 250- to 500- down activity against insects, paralysis is rapid, and fold more potent that lambda cyhalothrin and 175- to feeding damage to crops is minimal because insects 400-fold and 2,033 to 8,600-fold more potent than cease feeding shortly after ingestion. Avermectins fenvalerate to these two Lepidoptera, respectively intoxicate arthropods via contact and ingestion, (Jansson et al., 1997). More recent studes showed that although ingestion is considered to be the primary emamectin benzoate was 1.2- to 4.8-orders of route whereby arthropods accumulate a lethal dose. magnitude more potent to lepidopterous pests of cole The wide margin of safety for avermectin compounds crops (e.g. S. exigua, diamondback moth, Plutella to mammals is attributed to (1) the lack of glutamate- xylostella (L.), and cabbage looper, Trichoplusia ni gated chloride channels in mammals; (2) the low (Hubner) than other new insecticides, including affinity of avermectins for other mammalian ligand- chlorfenapyr, fipronil, and tebufenozide (Figure 2). gated chloride channels; and (3) their inability to Emamectin benzoate is markedly less toxic to readily cross the blood-brain barrier (Arena et al., most non-lepidopterous arthropods (Table 1). It is 1995). about 8- to 15-fold less toxic to the serpentine leafminer, Liriomyza trifolii (Burgess) and the two Potency and spectrum of activity of emamectin spotted spider mite, Tetrancychus urticae (Koch), benzoate respectively, than abamectin (Cox et al., 1995a; Dybas Emamectin benzoate is highly potent to a broad et al., 1989). Emamectin benzoate and abamectin are spectrum of lepidopterous pests. LC90 values for comparable in their potency against Mexican bean emamectin benzoate against a veriety of lepidopterous beetle, Epilachna varivestis Mulsant, and Colorado

172 Proceedings: The Management of Diamondback Moth and Other Crucifer Pests Potency Ratio (log10)

5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 S. exigua P. xylostella T. ni Emamectin Chlorfenapyr Fipronil Tebufenozide

Figure 2. Log10-transformed ratio of the LC90 value of chlorfenapyr, fipronil, or tebufenozide divided by the LC90 value for emamectin benzoate against three lepidopterous pests of cabbage. LC values were generated using an agar-based artificial diet assay in which different concentrations of each compound were applied to the surface of the diet (Jansson et al., 1997).

Table 1. Comparative toxicity of abamectin and emamectin benzoate to different pests of agricultural importance µ LC90 g/ml Arthropod species Abamectin Emamectin Benzoate PR* Acarina Foliar spray/contact assay Tetranychus urticae, adults 0.03c 0.29d 0.07 Insecta Coleoptera Leptinotarsa decemlineata, neonates, foliar spray 0.03c 0.03d 1.0 Epilachna varivestis, neonates, foliar spray 0.2c 0.2d 1.0 Diptera Liriomyza trifolii, first instar, plant dip 0.19f 1.45f 0.13 Homoptera Aphis fabae, foliar spray/contact 0.2Ð0.5g 19.9d 0.01Ð0.02 Lepidoptera Manduca sexta, neonates, foliar spray 0.02c 0.003d 7 Plutella xylostella, neonates, foliar spray 0.02g 0.002g 10 Heliothis virescens, neonates, foliar spray 0.13d 0.003d 43 Trichoplusia ni, neonates, foliar spray 1.0c 0.014d 71 Helicoverpa zea, neonates, foliar spray 1.5c 0.002d 750 Spodoptera exigua, neonates, foliar spray 1.97g 0.005d 394 Spodoptera eridania, neonates, foliar spray 6.0c 0.005d 1,200 Spodoptera frugiperda, neonates, foliar spray 25.0c 0.010d 2,500 Pseudoplusia includens, neonates, foliar spray Ð 0.019g Ð Ostrinia nubilalis, neonates, diet assay Ð 0.024g Ð Agrotis ipsilon, neonates, diet assay Ð 0.041g Ð Argyrotaenia velutinana, neonates, foliar spray Ð 0.009g Ð Cydia pomonella, neonates, diet 135.0h 0.89h 152 a PR, potency ratio = LC90 abamectin/LC90 emamectin benzoate bRoyalty and Perring (1987) cDybas and Green (1984) dDybas et al. (1989) eDybas (1989) fCox et al. (1995a) gMerck, unpublished data hCox et al. (1995b)

Chemical control 173 potato beetle, Leptinostarsa decemlineata (Say) efficacy of emamectin benzoate (8.4, 11.2, and 16.8 g (Dybas, 1989). Emamectin benzoate is markedly less ai/ha) with methomyl (504 g ai/ha), permethrin (112 toxic to black bean aphid, Aphis fabae Scopoli, than g ai/ha), and methomyl (504 g ai/ha) in combination abamectin (Table 1). with permethrin (112 g ai/ha), emamectin benzoate Like abamectin, emamectin benzoate is less toxic was superior to the other insecticides at controlling to most beneficial arthropods (e.g., honey bees, all lepidopterous pests (P. xylostella, T. ni, S. exigua) parasitoids, predators), especially when exposure on cole crops and resulted in higher percentages of occurs beyond one day after application (Lasota and marketable heads than all other insecticides tested Dybas, 1991 and references therein; Cox et al., (Figure 3). All three rates of emamectin benzoate were unpublished). Foliar residues of emamectin benzoate equal in their effectiveness at controlling these pests. were only slightly toxic (<20% mortality) to most Similar results were found when only data from trials beneficial insects, including honey bees, Apis that included P. xylostella were included (16 trials) mellifera, and several predtors and parasitoids, within (Figure 4). In 21 other field trials conducted to one day after application and often within a few hours compare the effectiveness of emamectin benzoate (8.4 after application (Cox et al., unpublished). The low g ai/ha) with biological insecticides, Bacillus toxicity was related to the short half-life of emamectin thuringensis (Berliner) ssp. aizawai (XenTari, 1,120 benzoate on foliage. On celery, the half-life of foliar g ai product/ha), B. thuringiensis ssp. kurstaki (Dipel, dislodgeable residues was estimated to be 1,120 g ai product/ha), and treatment regimes that approximately 0.66 days (Dunbar et al., unpublished). rotated two consecutive weekly applications of Kok et al. (1996) showed that emamectin emamectin benzoate with two consecutive weekly hydrochloride (MK-0234) displayed minimal adverse applications of XenTari, emamectin benzoate was effects against two hymenopterous parasitoids superior to B. thuringiensis ssp. aizawai (Figure 5). (Pteromalus puparum and Cotesia orobenae) on Similar results were found in Florida (Leibee et al., broccoli. Like abamectin, emamectin benzoate 1995). Collectively, these data demonstrate that provides ecological selectivity (and in some cases emamectin benzoate produces superior efficacy at physiological selectivity) to a wide range of beneficial controlling a broad spectrum of lepidopterous pests arthropods. For this reason, it is compatible with and increases in yield of cole crops compared with integrated management (IPM) programs. other commonly used chemical and biological insecticides. Photostability and translaminar movement Abamectin and emamectin benzoate are very Cross resistance and resistance management susceptible to photodegradation. MacConnell et al. Cross resistance between abamectin and amamectin (1989) showed that the half-life of abamectin was <10 benzoate and other classes of chemistry has not been h in simulated sunlight and that there were marked documented widely, nor is it well understood. Recent differences in the half-life of abamectin on Petri dishes studies by Lasota et al. (1996) showed that there was and on leaves in light and dark environments. The half- no cross resistance between abamectin, emamectin life of emamectin benzoate on celery has been benzoate, permethrin and methomyl in P. xylostella estimated to be 0.66 days; on cole crops, the half-life using an ingestion bioassay. Additional evidence from is expected to be even shorter. Numerous studies conducted at Merck Research Laboratories also photodegradates of emamectin benzoate have been suggested that there was no cross resistance between identified (Feely et al., 1992). abamectin and emamectin benzoate in T. urticae and Despite the short half-life for avermectin L. trifolii (Jansson et al., unpublished); however, more insecticides in sunlight, low levels of these compounds work is needed to confirm this belief. are taken up rapidly via translaminar movement into Pro-active resistance management programs were foliage. Translaminar movement of abamectin has developed for abamectin. Similar programs are being been demonstrated in numerous studies (Dybas, 1989 formulated for emamectin benzoate. Part of this pro- and references therein: Wright et al., 1985). Presence active strategy includes the development of monitoring of abamectin and emamectin benzoate reservoirs in systems to detect resistance in high risk populations parenchyma tissue accounts for their long residual of arthropods. Baseline data for susceptibility of P. activity on certain crops under field conditions, and xylostella populations to emamectin benzoate have their ability to control several Dipteran and been generated (Lasota et al., 1996). Monitoring Lepidopteran leafminers (Jansson & Dybas 1996). programs for P. xylostella and other problematic Lepidoptera are planned. Field efficacy To minimize the risk of resistance to emamectin Excellent efficacy of this compound at low use rates benzoate in lepidopterous pests, most product labels (7.5Ð16.8 g ai/ha) has been demonstrated against will provide restrictions on the type, number, and numerous lepidopterous pests in a variety of crops sequencing of applications allowed per growing (Jansson and Lecrone, 1991; Jansson et al.,1996; season. In addition, applications should be excluded Leibee et al., 1995; Merck, unpublished). Results from from transplant nurseries of certain vegetable crops numerous field trials conducted in cruciferous crops to reduce selection pressure on arthropods that pose were very consistent. In 29 trials conducted to compare the greatest risk (e.g. P. xylostella). These and other

174 Proceedings: The Management of Diamondback Moth and Other Crucifer Pests Percentage control of all Lepidoptera (29 trials)

a a 100 a bb 90 80 c 70 60

50 40 30

20 10 0 Emamectin Emamectin Emamectin Methomyl Permethrin Meth 504 g + 8.4 g 11.2 g 16.8 g 504 g 112 g Perm 112 g Insecticide treatments Percentage marketable heads (24 trials)

a a 100 a

90 bb 80 b 70

60

50 c 40 30 20

10

0 Emamectin Emamectin Emamectin Methomyl Permethrin Meth 504 g + Nontreated 8.4 g 11.2 g 16.8 g 504 g 112 g Perm 112 g Insecticide treatments Figure 3. Percentage control of all lepidopterous pests (compared with nontreated plants) (top) and percentage marketable heads (bottom) per treatment in cabbage plots treat with different insecticides (emamectin benzoate, 8.4, 11.2, and 16.8 g ai/ha; methomyl, 504 g ai/ha; permethrin 112 g ai/ha; methomyl, 504 g ai/ha, in combination with permethrin, 112 g ai/ha). Data are from 29 (top) and 24 field trials (bottom). strategies, such as advocation of rotation of emamectin Campbell, W. C. (ed.) (1989). Ivermectin and abamectin. benzoate with ohter chemical and biological Springer, New York, 363 pp. insecticides with different modes of action, and Cox, D. L., Remick, D., Lasota, J.A. and Dybas, R. A. advocation of IPM programs in all crops, should help (1995a). Toxicity of avermectins to Liriomyza trifolii (Diptera: Agromyzidae) larvae and adults. Journal of to prolong the life of emamectin benzoate in the Economic Entomology 88: 1415Ð1419 commercial sector. Cox, D. L., Knight, A. L. , Biddinger, D. G., Lasota, J. A., Pikounis, B., Hull, L. A. and Dybas, R. A. (1995b). References Toxicity and field efficacy of avermectins against Arena, J. P. (1994). Expression of Caenorhabditis elegans (Lepidoptera: Tortricidae) on apples. mRNA in Xenophus oocytes: a model system to study Journal of Economic Entomology 88: 708Ð715 the mechanism of action of avermectins. Parasitology Cvetovich, R. J. Kelly, D. H., Di Michele, L. M., Shuman, Today 10: 35Ð37 R.F. and Grabowski, E. J. J. (1994). Synthesis of 4"- Arena, J. P., Liu, K. K., Paress, P. S., Frazier, E. G., Cully, epi-amino-4"-deoxyavermectins B1. Journal of Organic D. F., Mrozik, H. and Schaeffer, J. (1995). The Chemistry 59: 7704Ð7708 mechanism of action of avermectin in Caenorhabditis Dybas, R. A. (1989). Abamectin use in crop protection. In: elegans: correlation between activation of glutamate- Ivermectin and Abamectin (ed. W.C. Campbell) pp. sensitive chloride current, membrane binding and 287Ð310. Springer, New York biological activity. Journal of Parasitology 81: 286Ð 294

Chemical control 175 Percentage control, P. xylostella (16 trials)

a a a 100

90 80

70

60 b b 50 b 40 T. ni 30

20

10

0 Emamectin Emamectin Emamectin Methomyl Permethrin Meth 504 g + 8.4 g 11.2 g 16.8 g 504 g 112 g Perm 112 g Insecticide treatments Figure 4. Percentage control of P. xylostella populations (compared with nontreated plants) in cabbage plots treated with different insecticides (see Fig. 3 details). Data are from 16 field trials.

Percentage marketable (21 trials)

a 100 a 90 80 a 70 60 b

50 40

30 b 20

10

0 Emamectin Emamectin XenTari Dipel Nontreated 8.4 g 8.4 g R/ 1120 g 1120 g XenTari 1120 g Insecticide treatments Figure 5. Percentage marketable heads of cabbage plants treated with emamectin benzoate (8.4 g ai/ha), emamectin benzoate (8.4 g ai/ha) rotated at 2Ð3 weeks intervals with B. thuringiensis ssp. aizawai (XenTari, 1,120 g product/ha), B. thuringiensis ssp. aizawai (XenTari, 1,120 g product/ha), or B. thuringiensis ssp. kurstaki (Dipel, 1,120 g product/ha), and nontreated plants. Data are from 21 field trials.

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176 Proceedings: The Management of Diamondback Moth and Other Crucifer Pests Jansson, R. K. and Dybas, R. A. (1996). Avermectins, Leibee, G. L., Jansson, R. K., Nuessly, G. and Taylor, J. biochemical mode of action, biological activity, and (1995). Efficacy of emamectin benzoate and Bacillus agricultural importance. In: Insecticides with Novel thuringiensis for control of diamondback moth on Modes of Action: Mechanism and Application (ed. I. cabbage in Florida. Florida Entomologist 78: 82Ð96 Ishaaya) Springer, New York (in press). MacConnell, J. G., Demchak, R. J., Preiser, F. A. and Dybas, Jansson, R. K. and Lecrone, S. H. (1991). Efficacy of R. A. (1989). Relative stability, toxicity, and nonconventional insecticides for control of penetrability of abamectin and its 8,9-oxide. Journal diamondback moth, Plutella xylostella (L.), in 1991. of Agricultural and Food Chemistry 37: 1498Ð1501 Proceedings of the Florida State Horticultural Society Mrozik, H. (1994). Advances in research and development 104: 279Ð284 of avermectins. In: Natural and Engineered Pest Jansson, R. K., Halliday, W. R., Argentine, J. A. and Dybas, Management Agents, American Chemical Society R. A. (1997). Comparison of miniature and high volume Symposium Series No. 551. (ed. P. A. Hedin et al.) pp. bioassays for screening insecticides. Journal of 54Ð73. American Chemical Society, Washington Economic Entomology (in review) Mrozik, H., Eskola, P., Linn, B. O., Lusi, A., Shih, T. L., Jansson, R. K., Peterson, R. F., Mookerjee, P. K., Halliday, Tishler, M., Waksmunski, F. S., Wyvratt, M. J., Hilton, W. R. and Dybas, R. A. (1996). Efficacy of solid N. J., Andersen, T. E., Babu, J. R., Dybas, R. R., Preiser, formulations of emamectin benzoate at controlling F. A. and Fisher, M. H. (1989). Discovery of novel lepidopterous pests. Florida Entomologist 79: 434Ð449 avermectins with unprecedented insecticidal activity. Kok, L. T., Lasota, J. A., McAvoy, T. J. and Dybas, R. A. Experientia 45: 315Ð316 (1996). Residual foliar toxicity of 4"-epimethylamino- Rohrer, S. P. and Arena, J. P. (1995). Ivermectin interactions 4"-deoxyavermectin B1 hydrochloride (MK-243) and with invertebrate ion channels. In: Molecular Action selected commercial insecticides to adult of Insecticides on Ion Channels. American Chemical hymenopterous parasites, Pteromalus puparum Society Symposium series No. 591 (ed. J.M. Clark) pp. (Hymenoptera: Pteromalidae) and Cotesia orobenae 264Ð283. American Chemical Society, Washington, (Hymenoptera: Braconidae). Journal of Economic D.C. Entomology 89: 63Ð67 Royalty, R. N. and Perring, T. M. (1987). Comparative Lasota, J. A. and Dybas, R. A. (1991). Avermectins, a novel toxicity of acaricides to Aculops lycopersici and class of compounds: implications for use in arthropod Homeopronematurs anconai (Acari: Eirophydae, pest control. Annual Review of Entomology 36: 91Ð117 Tydeidae). Journal of Economic Entomology 80: 348Ð Lasota, J. A., Shelton, A. M., Bolognese, J. A. and Dybas, 351 R. A. (1996). Baseline toxicity of avermectins to Trumble, J. T., Moar, W. J., Babu, J. R. and Dybas, R. A. diamondback moth (Lepidoptera: Plutellidae) (1987). Laboratory bioassays of the acute and populations: implications for susceptibility monitoring. antifeedant effects of avermectin B1 and a related Journal of Economic Entomology 89: 33Ð38 analogue on Spodoptera exigua (Hubner). Journal of Larivieri, M., Aziz, M., Weimann, D., Ginoux, J., Gaxotte, Agricultural Entomology 4: 21Ð28 P., Vingtain, P., Beauvais, B., Derouin, F., Schulz-Key, Turner, M. J. and Schaeffer, J. M. (1989). Mode of action of H., Basset, D. and Sarfati, C. (1985). Double-blind ivermectin. In: Ivermectin and Abamectin (ed. W.C. study of ivermectin and in African Cambell) pp. 73Ð88. Springer, New York patients with ocular involvement. Lancet Wright, D. J., Loy, A., Green, A. S. J. and Dybas, R.A. 2: 174Ð177 (1985). The translaminar activity of abamectin (MK- 936) against mites and aphids. Med Fac Landbouww Rijksuniv Gent 50(2b): 633Ð637

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