Exploration of Novel Botanical Insecticide Leads: Synthesis and

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Exploration of Novel Botanical Insecticide Leads: Synthesis and Insecticidal Activity of #-Dihydroagarofuran Derivatives Ximei Zhao, Xin Xi, Zhan Hu, Wenjun Wu, and Jiwen Zhang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.5b05782 • Publication Date (Web): 06 Feb 2016 Downloaded from http://pubs.acs.org on February 8, 2016

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Journal of Agricultural and Food Chemistry

Exploration of Novel Botanical Insecticide Leads: Synthesis and Insecticidal Activity of β-Dihydroagarofuran Derivatives Ximei Zhao†, Xin Xi†, Zhan Hu†, Wenjun Wu‡, Jiwen Zhang*,†,‡ †

College of Science, Northwest A&F University, Yangling, Shaanxi, 712100, P. R. China

‡

Key Laboratory of Botanical Pesticide R & D in Shaanxi Province, Yangling, Shaanxi, 712100, P.

R. China *Corresponding author (Tel: +86-029-87092191; Fax: +86-029-87093987; E-mail: nwzjw@ nwsuaf.edu.cn)

1

ACS Paragon Plus Environment


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1

ABSTRACT: The discovery of novel leads and new mechanisms of action is of vital

2

significance to the development of pesticides. To explore lead compounds for

3

botanical insecticides, seventy-seven β-dihydroagarofuran derivatives were designed

4

and synthesized. Their structures were mainly confirmed by 1H NMR,

5

DEPT-135°, IR, MS and HRMS. Their insecticidal activity was evaluated against the

6

3rd instar larvae of Mythimna separata Walker, and the results indicated that, of these

7

derivatives, eight exhibited more promising insecticidal activity than the positive

8

control, celangulin-V. Particularly, compounds 5.7, 6.6 and 6.7 showed LD50 values of

9

37.9, 85.1 and 21.1 µg/g, respectively, which was much lower than that of

10

celangulin-V (327.6 µg/g). These results illustrated that β-dihydroagarofuran ketal

11

derivatives can be promising lead compounds for developing novel mechanism-based

12

and highly effective botanical insecticides. Moreover, some newly discovered

13

structure-activity relationships are discussed, which may provide some important

14

guidance for insecticides development.

15

KEYWORDS: β-dihydroagarofuran, novel lead, new mechanism, botanical

16

insecticide, insecticidal activity, structure-activity relationship

2


13

C NMR,

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17

INTRODUCTION

18

Currently, such problems in agriculture as pesticide resistance and pesticide

19

accumulation in crops and the environment due to long-term and widespread

20

application of synthetic agrochemicals have posed serious threat to human health,

21

which requires development of pesticides with new target sites and modes of action.1-3

22

Natural products and natural product-based compounds play a significant role in

23

novel pesticide discovery and development because they tend to possess different

24

target sites and modes of action from synthetic pesticides and they are usually

25

environmentally benign due to their unique sources.4-7

26

The Celastraceae family is indigenous to tropical and subtropical regions of the

27

world,8,9 and plant extracts from this family possess various bioactivities9,10 such as

28

insect antifeedant,11 insecticidal,12-14 anti-HIV,15 and antitumor16 activities. On the

29

basis of previous research, the most widespread and extensive bioactive components

30

of plant extracts from the Celastraceae are a wide spectrum of β-dihydroagarofuran

31

sesquiterpenoids characterized by a β-dihydroagarofuran skeleton.10 Celastrus

32

angulatus Maxim is a significant insecticidal plant of the Celastraceae in China, and

33

many β-dihydroagarofuran sesquiterpene polyol esters extracted from this plant

34

display excellent insecticidal activity against the oriental armyworm.9-14 Among the

35

β-dihydroagarofuran sesquiterpene polyol esters present in C. angulatus, many are

36

characterized by a 1β,2β,4α,6α,8β,9α,12-heptahydroxy-β-dihydroagarofuran, 1,

37

framework.10 Therefore, by hydrolysis of these β-dihydroagarofuran sesquiterpene

38

polyol esters, a large amount of 1 can be obtained, which can be further used for novel

39

lead exploration and development of botanical insecticides needed in agriculture.

40

Recently, our group reported the synthesis and insecticidal activity of 3



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41

1β,4α,6α,9α-tetrahydroxy-2β,12-epoxymethano-β-dihydroagarofuran, 2, and a series

42

of its structural modification derivatives with the same substituents at 1- and

43

6-positions from 1 and found that some target compounds exhibited excellent

44

insecticidal activity.17 In 2015, we further reported two series of structurally modified

45

products of 2 with different substituents at 1- and 6-positions as insecticidal agents

46

and discovered that most of the synthesized compounds displayed significant

47

insecticidal activity and that the length of the carbon chain of the substituents at

48

1-position had a great impact on the insecticidal activity.18 However, up to now, little

49

attention has been paid to the simultaneous structural modification of hydroxyls at 1-,

50

6- and 9-positions. Therefore, to further study the structure-activity relationships of

51

β-dihydroagarofuran sesquiterpenoids towards exploring lead compounds for

52

botanical insecticides,

53

β-dihydroagarofuran analogues with formal or ketal protective groups of both

54

hydroxyls at 1- and 9-positions, and their insecticidal activity was evaluated against

55

the 3rd instar larvae of Mythimna separata Walker (oriental armyworm) with the leaf

56

disc method. M. separata is a typical lepidopteran pest of crops such as wheat, corn

57

and rice, and often causes great crop yield losses because of high incidence of larvae

58

outbreaks.19,20

59

environmentally-benign method is very important to agriculture and human health.

60

MATERIALS AND METHODS

61

General

we

Therefore,

herein

the

designed

control

of

and

it

synthesized

with

an

seventy-seven

effective

and

62

All chemical reagents were purchased from commercial sources. Solvents such

63

as petroleum ether, dichloromethane, ethyl acetate, acetone, methanol and

64

tetrahydrofuran (THF) were purchased from Bodi Chemical Co., Ltd. (Tianjin, China), 4


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65

and all anhydrous solvents were dried with standard methods just before use. The

66

starting material 1β,2β,4α,6α,8β,9α,12-heptahydroxy-β-dihydroagarofuran, 1, (purity

67

≥ 98%) was provided by the Institute of Pesticide Science, Northwest A&F University

68

(Yangling, China). The reaction progress was monitored by thin layer chromatography

69

(TLC) analysis on GF254 silica gel plates (Qingdao Haiyang Chemical Co., Ltd.,

70

Qingdao, China), and the spots were observed by an ultraviolet lamp or 5% (v/v)

71

sulfuric acid in ethyl alcohol; the target compounds were purified by a

72

chromatography column (305 × 26 mm) (Beijing Synthware Glass Co., Ltd., Beijing,

73

China) with silica gel (zcx II, 200-300 mesh) (Qingdao Haiyang Chemical Co., Ltd.,

74

Qingdao, China), and mixtures of petroleum ether and ethyl acetate served as the

75

eluent. Melting points (mp) were obtained on a WRS-1B melting point apparatus

76

(Shanghai YiCe Apparatus and Equipment Co., Ltd, Shanghai, China); specific

77

rotations were determined on a 241 MC automatic polarimeter (PerkinElmer,

78

Waltham, MA); 1H NMR and

79

spectrometer (Bruker, Billerica, MA) at 500 MHz and 125 MHz in deuterochloroform

80

(CDCl3) with tetramethylsilane (TMS) as reference; distortionless enhancement by

81

polarization transfer (DEPT) spectra (flip angle of 135°) were measured to determine

82

the assignments of

83

TENSOR 27 spectrometer (Bruker Optics, Ettlingen, Germany); ESI-MS was

84

performed on an ESI-TRAP Esquire 6000 plus mass spectrometry instrument (Bruker,

85

Billerica, MA); high-resolution mass spectrometry (HRMS) was carried out on a LTQ

86

Orbitrap XL instrument (Thermo Scientific, Waltham, MA); the X-ray crystal

87

structures of 6.7 and 8.7 were obtained on a D8 VENTURE instrument (Bruker,

88

Karlsruhe, Germany).

89

Synthesis of Target Compounds 3.1-3.11, 4.1-4.11, 5.1-5.11, 6.1-6.11, 7.1-7.11,

13

13

C NMR spectra were recorded utilizing an Avance

C chemical shifts; infrared spectra (IR) were obtained on a

5



90

91

92

8.1-8.11, and 9.1-9.11. The synthesis of 2 was carried out as previously described.17,18 Synthesis of compound 3

93

A solution of 2 (300 mg, 1 mmol), paraformaldehyde (45 mg), and

94

p-toluenesulfonic acid (34.4 mg, 0.2 mmol) in 50 mL of dichloromethane was stirred

95

for 40 min at room temperature. The reaction was monitored by TLC. On completion,

96

the resulting mixture was washed with saturated sodium bicarbonate aqueous solution

97

and extracted with dichloromethane. The combined organic layer was separated,

98

washed with water and saturated sodium chloride aqueous solution, and dried over

99

anhydrous sodium sulfate. The solvent was removed under reduced pressure and the

100

residue was purified by silica gel column chromatography with petroleum ether and

101

ethyl acetate (v/v = 2:1) to produce 3 as a white solid (271 mg, yield 87%).

102

Synthesis of compounds 4-9

103

A solution of 2 (300 mg, 1 mmol), ferric chloride (8.11 mg, 0.05 mmol) and

104

acetone, 3-pentanone, 4-heptanone, 5-nonanone, cyclopentanone or cyclohexanone (5

105

mmol) in 50 mL of dichloromethane was stirred for 24 h at room temperature. The

106

reaction was monitored by TLC. On completion, the dichloromethane was removed

107

under reduced pressure and the residue was purified by silica gel column

108

chromatography with petroleum ether and ethyl acetate (v/v = 2:1) to give compounds

109

4-9 as white solids with 90-95% yields.

110

111

An alternative method for the synthesis of 4 has been reported.18 Synthesis of compound 3.1

6


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112

A mixture of 3 (40 mg, 0.13 mmol) and sodium hydride (31.4 mg, 1.31 mmol) in

113

10 mL of anhydrous THF was stirred for 30 min at room temperature. To this mixture

114

was added iodomethane (11.83 µL, 0.19 mmol), and the resulting mixture was stirred

115

for 30 min at room temperature. The reaction was monitored by TLC. On completion,

116

0.5 mL of water was added, and the THF was evaporated under reduced pressure. The

117

residue was then extracted with dichloromethane, washed with saturated sodium

118

chloride aqueous solution, and dried with anhydrous sodium sulfate. The

119

dichloromethane was removed under reduced pressure and the residue was

120

chromatographed with petroleum ether and ethyl acetate (v/v = 2:1) to give 3.1 as a

121

white solid (38 mg, yield 90%).

122

Synthesis of compounds 3.2-3.11

123

The target compounds 3.2-3.11 were synthesized using the method similar to that

124

used for compound 3.1 with corresponding halohydrocarbons, and the yields were

125

90-95%.

126

Alternative method for compounds 3.3-3.5 and 3.8-3.11

127

A solution of 3 (40 mg, 0.13 mmol) and sodium hydride (31.4 mg, 1.31 mmol) in

128

10 mL of anhydrous THF was stirred for 30 min at room temperature. To this solution

129

was added the corresponding halohydrocarbons (0.65 mmol), and the reaction mixture

130

was refluxed for 40 min. The reaction was monitored by TLC. On completion, the

131

mixture was cooled to room temperature, and 0.5 mL of water was added. The THF

132

was evaporated under reduced pressure. And the residue was then extracted with

133

dichloromethane, washed with saturated sodium chloride aqueous solution, and dried

134

with anhydrous sodium sulfate. The dichloromethane was removed under reduced

135

pressure and the residue was chromatographed with petroleum ether and ethyl acetate 7



136

(v/v = 4:1) to give the target compounds 3.3-3.5 and 3.8-3.11 with 90-95% yields.

137

Synthesis of compounds 4.1-4.11, 5.1-5.11, 6.1-6.11, 7.1-7.11, 8.1-8.11, and 9.1-9.11

138

Method 1: The target compounds 4.1-4.11, 5.1-5.11, 6.1-6.11, 7.1-7.11, 8.1-8.11,

139

and 9.1-9.11 were prepared according to the procedure similar to that of compound

140

3.1 using corresponding halohydrocarbons, and the yields were 90-95%.

141

Method 2: Alternative method for 4.3-4.5, 4.8-4.11, 5.3-5.5, 5.8-5.11, 6.3-6.5,

142

6.8-6.11, 7.3-7.5, 7.8-7.11, 8.3-8.5, 8.8-8.11, 9.3-9.5, and 9.8-9.11 was similar to that

143

used for the synthesis of 3.3-3.5 and 3.8-3.11.

144

Biological Assay

145

The insecticidal activity of compounds 3.1-3.11, 4.1-4.11, 5.1-5.11, 6.1-6.11,

146

7.1-7.11, 8.1-8.11, and 9.1-9.11 was evaluated against the 3rd instar larvae of M.

147

separata starved for 12 h using leaf disc method.12 In the primary bioassay, fresh

148

wheat or corn leaf discs (5 mm × 5mm) treated with 1.12 µL of a solution of the

149

derivatives at a concentration of 40 mg/mL in acetone were applied. For each

150

derivative, thirty larvae of M. separata were tested. Leaf discs treated with acetone

151

and celangulin-V served as blank and positive control, respectively. Mortality rates

152

were recorded within 36 h, and the toxicity was ascertained by establishing the

153

median lethal dose (LD50, the dose required to kill 50% of the population) of

154

compounds with insect mortality over 70%. In order to make the structure-activity

155

relationship more obvious, the LD50 value of compound 7.7 was also determined. In

156

this process, fresh wheat or corn leaf discs (5 mm × 5mm) treated with 1.12 µL of an

157

acetone solution of the derivatives at concentrations of 5, 10, 15, 20 and 25 mg/mL, or

158

7.7 at concentrations of 20, 25, 30, 35 and 40 mg/mL, were applied. For each bioassay,

8


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159

fifteen larvae of M. separata were tested. Leaf discs treated with acetone and

160

celangulin-V were used as blank and positive control, respectively. Mortality rates

161

were recorded within 36 h. The eaten area of a leaf was measured under a binocular

162

microscope,12 and the dose of the compound was calculated.

163

RESULTS AND DISCUSSION

164

Synthesis

165

The synthesis of the target compounds 3.1-3.11, 4.1-4.11, 5.1-5.11, 6.1-6.11,

166

7.1-7.11, 8.1-8.11, and 9.1-9.11 is shown in Figure 1. Specifically, the lead compound

167

2 was synthesized by the reaction of 1 with methanesulfonyl chloride and subsequent

168

reduction in the presence of lithium aluminium hydride (LAH). Afterwards, the

169

hydroxyl groups at 1- and 9-positions of 2 were protected either by formaldehyde

170

under the catalysis of p-toluenesulfonic acid (TsOH) to give 3 or by ketones including

171

acetone, 3-pentanone, 4-heptanone, 5-nonanone, cyclopentanone and cyclohexanone

172

under the catalysis of ferric chloride to produce 4-9, respectively. Finally, all the target

173

compounds 3.1-3.11, 4.1-4.11, 5.1-5.11, 6.1-6.11, 7.1-7.11, 8.1-8.11, and 9.1-9.11

174

were synthesized by reaction of 3-9 with sodium hydride in anhydrous THF and

175

subsequent treatment with various halohydrocarbons.

176

Insecticidal Activity

177

The insecticidal activity of the target compounds 3.1-3.11, 4.1-4.11, 5.1-5.11,

178

6.1-6.11, 7.1-7.11, 8.1-8.11, and 9.1-9.11 against the 3rd instar larvae of M. separata

179

was evaluated with the leaf disc method. Acetone and celangulin-V were used as

180

blank and positive control, respectively. The bioassay results are summarized in

181

Tables 1 and 2. The LD50 values were considered to be significantly different if the 9



182

95% confidence intervals (CI) did not overlap (Table 2).

183

As shown in Table 1, many of the target compounds with long-chain protective

184

groups exhibited excellent insecticidal activity against the 3rd instar larvae of M.

185

separata, especially compounds 3.7, 3.8, 3.10, 3.11, 4.7, 4.10, 5.7, 6.3, 6.6, 6.7, 7.3

186

and 7.6 with 83.3%, 91.7%, 91.7%, 91.7%, 91.7%, 91.7%, 100.0%, 75.0%, 75.0%,

187

83.3%, 83.3% and 91.7% insect mortality, respectively. Compounds 5.7, 6.6 and 6.7

188

displayed LD50 values of 37.9, 85.1 and 21.1 µg/g, respectively, which was much

189

lower than that of celangulin-V (327.6 µg/g) (Table 2). Compounds 3.10 and 4.7 also

190

displayed potent insecticidal activity with LD50 values of 186.6 and 123.7 µg/g,

191

respectively. In addition, compounds 3.8, 6.3 and 7.6 showed good insecticidal

192

activity with LD50 values similar to that of celangulin-V (Table 2).

193

However, for derivatives bearing cyclic protective groups, most of them

194

displayed a little or even no insecticidal activity against the 3rd instar larvae of M.

195

separata (Table 1). Even compound 8.7 with insect mortality of 83.3% just displayed

196

LD50 value of 172.3 µg/g (Table 2), much higher than that of compound 5.7 (37.9

197

µg/g).

198

During the bioassay process, a series of specific symptoms in the test larvae were

199

observed (Figure 2) and they were summarized as follows: compared to larvae used

200

for blank control, the bodies of the poisoned ones were narcotized, soft and

201

immobilized at first; then diarrhea and vomiting with some colorless liquid were

202

observed around the bodies of the larvae; finally, the liquid evaporated, and the larvae

203

were poisoned completely to death. These symptoms resembled those caused by

204

celangulin-V and its derivatives.21,22 Therefore, we concluded that the target

205

derivatives acted on the midgut tissue of the test oriental armyworm larvae and caused 10


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206

the death, just as the mechanism of toxicology of celangulin-V.3

207

Structure-Activity Relationship

208

The bioassay results demonstrated that the variety of protective groups

209

significantly affected the insecticidal activity of the target compounds. Specifically,

210

the long-chain protective groups were more beneficial than cyclic ones to the

211

development of insecticidal activity of the derivatives. For example, in Table 1, many

212

of the target compounds with long-chain protective groups exhibited excellent

213

insecticidal activity with insect mortality over 75% and some even over 90%, whereas

214

most of the target compounds bearing cyclic protective groups showed little or even

215

no bioactivity and only compound 8.7 exhibited 83.3% insect mortality. However, as

216

shown in Table 2, the LD50 value of 8.7 (172.3 µg/g) was still much higher than that

217

of compound 5.7 (37.9 µg/g). As depicted in Figure 1, the only difference in the

218

structures between 8.7 and 5.7 was whether the protective group was a ring or a chain.

219

Therefore, the big difference in the LD50 values between 8.7 and 5.7 exactly

220

demonstrates the structure-activity relationship mentioned above. The possible reason

221

for the ineffectiveness of compounds with cyclic protective groups was that the rigid

222

structure of ring hindered the binding of target compound with its target protein,

223

which resulted in the loss of activity of those derivatives, and this hindrance became

224

stronger with the expansion of the ring. For example, compared to compounds

225

8.1-8.11, compounds 9.1-9.11 exhibited much lower insect mortality and more

226

compounds displayed zero mortality. Moreover, as for derivatives bearing long-chain

227

protective groups, their insecticidal activity was significantly influenced by the length

228

of the protective carbon chain. Specifically, with the increase in the length of the

229

protective carbon chain, the insecticidal activity of the derivatives first increased and

230

then decreased, reaching a maximum when the protective group consisted of seven 11



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231

carbon atoms. As shown in Table 2, when the moiety at the 6-position was a propargyl

232

group, the LD50 values of the target compounds first decreased and then increased

233

with the rise in the length of the protective carbon chain, reaching a minimum at 21.1

234

µg/g when the chain consisted of seven carbon atoms. The bioassay results revealed

235

that

236

β-dihydroagarofuran, which was in accordance with the structure-activity relationship

237

demonstrated in our previous work.17 Interestingly, the benzyl group with a fluorine at

238

p- or o-positions, which proved to be promising bioactive groups in our previous

239

study,15 exhibited good to moderate insecticidal activity only when the protective

240

group consisted of one or three carbon atoms (3.10, 3.11 and 4.10).

the

propargyl

group

was

a

bioactive

group

for

the

skeleton

of

In conclusion, this work indicates that β-dihydroagarofuran ketal derivatives can

241 242

be

243

environmentally-benign and highly effective botanical insecticides urgently needed in

244

agriculture, and the newly discussed structure-activity relationships also provide some

245

important hints for further design, synthesis and structural modification of

246

β-dihydroagarofuran sesquiterpenoids as botanical insecticidal agents.

247

ASSOCIATED CONTENT

248

Supporting Information Available

249

promising

1

H and

13

lead

compounds

for

developing

novel

mechanism-based,

C NMR spectra for target compounds with LD50 values in Table 2.

250

Yield, melting point (mp), optical rotation, 1H NMR,

13

251

data for the target compounds 3.1-3.11, 4.1-4.11, 5.1-5.11, 6.1-6.11, 7.1-7.11, 8.1-8.11,

252

and 9.1-9.11, and the X-ray crystallographic data for compounds 6.7 and 8.7. This

253

material is available free of charge via the Internet at http://pubs.acs.org.

C NMR, IR, MS and HRMS

12


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254

AUTHOR INFORMATION

255

Corresponding Author

256

*(J. W. Zhang) Telephone: +86-029-87092191. Fax: +86-029-87093987. E-mail:

257

[email protected].

258

Funding

259

This work was financially supported by the National Natural Science Foundation

260

of China (31371958, 21372185) and the National Key S&T Research Foundation of

261

China (2010CB126105).

262

Notes

263

The authors declare no competing financial interest.

13



264

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265

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insecticidal sesquiterpenoids from Celastrus angulatus. J. Nat. Prod. 2001, 64,

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FIGURE CAPTIONS

323

Figure 1. Synthesis of target compounds

324

Figure 2. Larva at various stages of poisoning: A. Blank control larva; B. Poisoned

325

larva with narcotized, soft and immobile body; C. Vomiting larva with colorless liquid

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around the mouth; D. Diarrheal and vomiting larva with colorless liquid around the

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body; E. Completely poisoned larva.

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TABLES Table 1. Insecticidal Activity of the Target Compounds Against the 3rd Instar Larvae of M. separata at a Concentration of 40 mg/mL Within 36 h

Compounds 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 5.1 5.2 5.3 5.4 Acetone

Mortality (%) Mortality (%) Mortality (%) Compounds Compounds ± SD (%) ± SD (%) ± SD (%) 0.0 ± 0.0 33.3 ± 2.9 5.5 41.7 ± 2.3 50.0 ± 3.2 5.6 41.7 ± 3.2 100.0 ± 4.0 5.7 66.7 ± 2.6 25.0 ± 2.6 5.8 33.3 ± 2.9 25.0 ± 3.1 5.9 33.3 ± 3.3 50.0 ± 3.5 5.10 83.3 ± 3.7 67.0 ± 3.6 5.11 91.7 ± 2.5 50.0 ± 2.3 6.1 50.0 ± 2.2 58.3 ± 2.6 6.2 91.7 ± 3.0 75.0 ± 3.4 6.3 91.7 ± 3.2 66.7 ± 3.6 6.4 25.0 ± 2.1 33.3 ± 4.2 6.5 41.7 ± 3.2 75.0 ± 3.5 6.6 41.7 ± 3.5 83.3 ± 2.8 6.7 33.3 ± 2.4 8.3 ± 3.9 6.8 33.3 ± 3.6 50.0 ± 3.4 6.9 58.3 ± 4.2 25.0 ± 2.7 6.10 91.7 ± 3.1 25.0 ± 4.3 6.11 58.3 ± 3.3 41.7 ± 4.3 7.1 33.3 ± 2.6 50.0 ± 4.6 7.2 91.7 ± 2.5 83.3 ± 3.5 7.3 61.0 ± 3.4 25.0 ± 2.8 7.4 33.3 ± 3.5 8.3 ± 3.4 7.5 66.7 ± 3.8 91.7 ± 4.6 7.6 50.0 ± 4.4 66.7 ± 2.9 7.7 58.3 ± 4.7 33.3 ± 3.3 7.8 0.0 ± 0.0 Celangulin-V 91.7 ± 2.5

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7.9 7.10 7.11 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10 9.11

33.3 ± 3.5 16.7 ± 2.4 33.3 ± 3.7 8.3 ± 3.2 16.7 ± 3.5 0.0 ± 0.0 16.7 ± 4.5 33.3 ± 3.3 58.3 ± 2.2 83.3 ± 2.6 0.0 ± 0.0 8.3 ± 3.2 0.0 ± 0.0 64.0 ± 2.3 0.0 ± 0.0 8.3 ± 2.1 0.0 ± 0.0 16.7 ± 2.4 25.0 ± 3.3 16.7 ± 3.6 25.0 ± 4.2 0.0 ± 0.0 0.0 ± 0.0 0.0 ± 0.0 24.0 ± 3.2

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Table 2. LD50 Values of the Target Compounds Against the 3rd Instar Larvae of M. separata Within 36 h Compds

LD50 (µg/g)

Compds

LD50 (µg/g)

-a 5.5 5.6 5.7 37.9 (31.7-45.1) 5.8 5.9 5.10 539.2 (363.9-799.2)b 5.11 375.7 (290.7-485.8) 6.1 6.2 186.6 (147.2-236.7) 280.4 (238.3-329.9) 6.3 870.9 (738.3-1026.7) 6.4 6.5 85.1 (72.8-99.5) 6.6 21.1 (17.6-25.3) 6.7 6.8 6.9 6.10 123.7 (106.0-143.5) 6.11 7.1 7.2 429.8 (362.3-510.1) 431.5 (364.2-511.3) 7.3 7.4 7.5 253.8 (210.0-306.7) 7.6 2555.8 (2026.0-3224.0) 7.7 7.8 Celangulin- 327.6 (275.1-390.3) Acetone V 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10 4.11 5.1 5.2 5.3 5.4

a

A dash (-) indicates that the LD50 was not measured.

b

The 95% confidence intervals (CI) are put in parentheses.

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Compds

LD50 (µg/g)

7.9 7.10 7.11 8.1 8.2 8.3 8.4 8.5 8.6 8.7 172.3 (140.3-211.6) 8.8 8.9 8.10 8.11 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 9.10 9.11


FIGURE GRAPHICS

Figure 1 20


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A

B

D

E

C

Figure 2

21



TABLE OF CONTENTS GRAPHIC

C C

22


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Exploration of Novel Botanical Insecticide Leads: Synthesis and

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