Pest Management Science

Pest Manag Sci 63:928934 (2007)

Lead optimization and insecticidal activity of analogues of daphneolone isolated from Stellera chamaejasme L.
Lin Chen,1 Xinliang Wang,2 Tao Lu1 and Taiping Hou1
1 Key

Laboratory of Bio-Resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China 2 College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637002, China

Abstract: Starting from the chemical structure of the botanical aphicides 1,5-diphenyl-1-pentanone and 1,5diphenyl-2-penten-1-one, extracted from Stellera chamaejasme L., the authors designed and synthesized a series of novel compounds following the concept of bioisosterism. Their structures were established on the basis of 1 H NMR and GC-MS spectra, and the insecticidal activities of the compounds were evaluated against Aphis gossypii Glover. The results demonstrated that the substitution of a heterocycle for the phenyl ring was favourable. Thus, further modication of compound 2n, containing a furan ring, which showed excellent activity (LC50 = 0.85 g L1 ), is of some promise. 2007 Society of Chemical Industry

Keywords: Stellera chamaejasme; synthesis; insecticidal activity; aphicide

1 INTRODUCTION The cotton aphid, Aphis gossypii Glover, is a major economic pest in agriculture in China and other areas of the world. The insecticide market has been generally dominated since the 1970s by three chemical classes of organophosphates, carbamates and synthetic pyrethroids. However, strategies to control aphids with classic aphicides may produce side effects, notably environmental contamination and the development of multiresistant strains.1 3 Thus, it is desirable to develop new insecticidal agents that are both active against resistant strains and safe to humans and the environment. Botanical insecticides play an important role in controlling pests. However, botanical insecticides have some drawbacks such as low yield, instability, complex components and limited insecticidal spectrum. Thus, a plant extract is often used as a lead structure for synthesizing a novel class of insecticides.4 7 In 2001, researchers at Sichuan University described for the rst time the insecticidal properties of 1,5diphenyl-1-pentanone and 1,5-diphenyl-2-penten-1one (Fig. 1), which were extracted from Stellera chamaejasme L. (Thymelaeaceae, used in Chinese traditional medicine).8 Laboratory bioassay showed that the two products have strong contact activity and very good antifeedant activity against A. gossypii and Schizaphis graminum Rondani.9,10 Moreover, products a and b at a dose of 2 g kg1 per os did not cause any toxic effects in mice, rats or rabbits. These products

are similar in structure to daphneolone11 (the nematicidal substance extracted from Daphne odora Thunb), chalcones, dihydrochalcones,12 14 2-phenylethyl benzoate, dibenzyl ketone15 and avonoids. Most of these compounds contain a phenylcarbonylphenyl skeleton, indicating that this may be important for insecticidal activity. In addition, bioisosterism16 is a rational approach in drug design. This bioisosteric replacement could induce several modications in terms of size, shape, electronic distribution, lipophilicity, chemical reactivity and hydrogen bonding capacity. Among these physicochemical modications, chemical and biochemical aspects could be of major interest. Thus, with this structure in mind, and on the basis of the principle of bioisosterism, the authors designed and synthesized a series of novel compounds (Figs 2 and 3) to identify potential new insecticides. The present paper is concerned with the synthesis and insecticidal activity of these title compounds. In addition, structureactivity relationships for selected substitution patterns are discussed.

2 EXPERIMENTAL 2.1 General 1 H-Nuclear magnetic resonance (NMR) spectra were recorded in deuterochloroform solution with a Varian Unity Inova-400 instrument (Varian, Palo Alto, CA), using tetramethylsilane (TMS) as an internal standard.

Correspondence to: Taiping Hou, Key Laboratory of Bio-Resource and Eco-environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China E-mail: yeoni329@hotmail.com Contract/grant sponsor: National Natural Science Foundation of China; contract/grant number: 20372052 and 20572076 Contract/grant sponsor: Hi-Tech Research and Development of China; contract/grant number: 2006AA10A209 (Received 18 August 2006; revised version received 25 January 2007; accepted 26 January 2007) Published online 18 June 2007; DOI: 10.1002/ps.1399

2007 Society of Chemical Industry. Pest Manag Sci 1526498X/2007/$30.00

Insecticidal activity of daphneolone analogues

O O H

H a: 1, 5-Diphenyl-1-pentanone b: 1, 5-Diphenyl-2-penten-1-one

Figure 1. Compounds a and b extracted from Stellera chamaejasme L.

Mass spectra were recorded with a Thermonnigan Polaris-Q GC-MS instrument (Shimazu, Japan). Solvents and reagents were obtained from commercial sources and used without further purication. 2.2 Synthesis of title compounds The title compounds were synthesized according to the route shown in Figs 2 and 3, and the yields were not optimized. Some starting benzoic acids were not commercially available and were prepared as follows. 4-Methoxybenzoic acid was formed by a solvent-free Cannizzaro17 reaction. 2Methoxybenzoic acid, 2-hydroxy-4-methoxybenzoic acid, 3,4-dimethoxybenzoic acid and 3,4,5trimethoxybenzoic acid were prepared by treatment of the corresponding hydroxybenzoic acid with dimethyl sulfate.18 5-Chlorosalicylic acid was synthesized by halogenation of salicylic acid in acetic acid.18 2.2.1 Carboxylic acid chlorides The corresponding acid and 1.52.0 equivalent of thionyl chloride were heated for 0.51 h under reux. When the reaction was complete, the excess thionyl chloride and the solvent were distilled off under reduced pressure. The yields of the crude products were 9599%. 2.2.2 General procedure for 1a1f: synthesis of 2-hydroxy-N-phenethylbenzamide (1a) A mixture of aqueous sodium hydroxide solution (100 g L1 , 2 mL) and 2-phenylethanamine (0.60 g, 5 mmol) was cooled to 810 C, and then 2hydroxybenzoyl chloride (0.63 g, 4 mmol) (prepared from benzoic acid) was slowly added under stirring. At the same time, aqueous sodium hydroxide solution (100 g L1 , 4 mL) was added. The resulting reaction mixture was stirred for 2 h at 55 C, and then the precipitate was ltered off, washed with water and
O R OH O R Cl H N O 1a-1f

evaporated under vacuum. The other acyl derivatives of 2-phenylethylamine were synthesized in a similar way. When the mixture was an oily material, the product was extracted with diethyl ether. Finally, the combined organic layers were washed with water, dried over magnesium sulfate and isolated by column chromatography on silica gel with hexane + ethyl acetate (2 + 1 by volume). Compound 1a was obtained as a white solid (0.54 g, 56.4%); 1 H NMR (400 MHz) : 2.927 (t, 2H, CH2 ), 3.7473.698 (m, 2H, CH2 ), 6.280 (bs, 1H, NH), 6.7806.821 (m, 1H, ArH), 6.981 (q, 1H, ArH), 7.0257.298 (m, 5H, ArH), 7.3277.401 (m, 2H, ArH), 12.325 (s, 1H, ArOH); MS m/z (%): 51 (2), 65 (14), 77 (3), 93 (9), 104 (13), 121 (100), 137 (5), 150 (19), 241 (M+ 3). 2.2.2.1 2-Bromo-N-phenethylbenzamide (1b). The compound was obtained in 58.0% yield as a white solid; 1 H NMR (400 MHz) : 2.965 (t, 2H, CH2 ), 3.7363.786 (m, 2H, CH2 ), 6.209 (bs, 1H, NH), 7.2047.362 (m, 8H, ArH), 7.5327.652 (m, 1H, ArH); MS m/z (%): 50 (7), 65 (8), 91 (15), 103 (5), 104 (100), 105 (15), 156 (16), 182 (66), 183 (6), 184 (64), 185 (5), 211 (13), 213 (12), 302 (21), 304 (4), 305 (M+ 20). 2.2.2.2 2-Methoxy-N-phenethylbenzamide (1c). The compound was obtained in 21.5% yield as a greenyellow oil; 1 H NMR (400 MHz) : 2.932 (t, 2H, CH2 ), 3.7293.792 (m, 2H, CH2 ), 3.750 (d, 3H, ArOCH3 ), 6.911 (q, 1H, ArH), 7.0467.087 (m, 1H, ArH), 7.2357.361 (m, 5H, ArH), 7.3967.439 (m, 1H, ArH), 7.899 (bs, 1H, NH), 8.212 (q, 1H, ArH); MS m/z (%): 51 (3), 65 (3), 77 (20), 92 (8), 104 (6), 134 (4), 135 (100), 136 (9), 164 (17), 255 (M+ 15). 2.2.2.3 2-Ethoxy-N-phenethylbenzamide (1d). The compound was obtained in 38.3% yield as a paleyellow oil; 1 H NMR (400 MHz) : 1.205 (t, 3H, CH3 ), 2.936 (t, 2H, CH2 ), 3.7273.790 (m, 2H, CH2 ), 4.050 (q, 2H, CH2 ), 6.900 (q, 1H, ArH), 7.0377.077 (m, 1H, ArH), 7.2087.334 (m, 5H, ArH), 7.3737.417 (m, 1H, ArH), 8.085 (bs, 1H, NH), 8.238 (q, 1H, ArH); MS m/z (%): 51 (3), 65 (4), 77 (21), 92 (6), 104 (7), 149 (100), 178 (16), 269 (M+ 16). 2.2.2.4 2-Chloro-N-phenethylbenzamide (1e). The compound was obtained in 41.2% yield as a white solid; 1 H NMR (400 MHz) : 2.965 (t, 2H, CH2 ), 3.7363.786 (m, 2H, CH2 ), 6.189 (bs, 1H, NH), 7.2217.380 (m, 8H, ArH), 7.6007.622 (m, 1H, ArH); MS m/z (%): 51 (4), 65 (6), 75 (11), 91 (10), 104 (70), 139 (100), 168 (15), 259 (M+ 27). 2.2.2.5 N-phenethylfuran-2-carboxamide (1f). The compound was obtained in 31.9% yield as a yellow oil; 1 H NMR (400 MHz) : 2.912 (t, 2H,
929

SOCl2

NH2 R

Figure 2. Synthesis route for compounds 1a1f.

O R OH

OH conc.H2SO4 R

O O 2a-2n

Figure 3. Synthesis route for compounds 2a2n.

Pest Manag Sci 63:928934 (2007) DOI: 10.1002/ps

L Chen et al.

CH2 ), 3.6633.714 (m, 2H, CH2 ), 6.401 (bs, 1H, NH), 6.479 (q, 1H, FuH), 7.089 (q, 1H, FuH), 7.2287.349 (m, 5H, ArH), 7.392 (q, 1H, FuH); MS m/z (%): 65 (5), 77 (3), 95 (100), 104 (42), 124 (34), 186 (6), 215 (M+ 22). 2.2.3 General procedure for 2a2n: synthesis of 3-phenylpropyl 4-chlorobenzoate (2a) 4-Chlorobenzoic acid (0.62 g, 4 mmol) was suspended in 3-phenylpropan-1-ol (1.09 g, 8 mmol), and concentrated sulfuric acid (0.05 mL) was added dropwise under stirring. The mixture was stirred for 4 h at 120 C and then cooled and poured into a mixture of crushed ice (5 mL) and aqueous sodium bicarbonate solution (100 g L1 , 10 mL). After separation of the phases, the aqueous layer was extracted with diethyl ether (3 5 mL). The combined organic layers were washed with water (3 5 mL), dried over magnesium sulfate and isolated by column chromatography on silica gel with hexane + ethyl acetate (8 + 1 by volume). Compound 2a was obtained as a yellow oil (0.88 g, 80.5%); 1 H NMR (400 MHz) : 2.105 (m, 2H, CH2 ), 2.781 (t, 2H, CH2 ), 4.337 (t, 2H, CH2 ), 7.1837.315 (m, 5H, ArH), 7.409 (m, 2H, JH = 8.4 Hz, JH = 2.0 Hz, ArH), 7.946 (m, 2H, JH = 8.4 Hz, JH = 2.0 Hz, ArH); MS m/z (%): 51 (3), 65 (5), 75 (7), 91 (17), 111 (13), 117 (70), 118 (100), 139 (15), 274 (M+ 1). 2.2.3.1 3-Phenylpropyl 2-hydroxybenzoate (2b). The compound was obtained in 44.8% yield as a yellow oil; 1 H NMR (400 MHz) : 2.123 (m, 2H, CH2 ), 2.793 (t, 2H, CH2 ), 4.361 (t, 2H, CH2 ), 6.882 (m, 1H, ArH), 6.992 (q, 1H, ArH), 7.1887.320 (m, 5H, ArH), 7.456 (m, 1H, ArH), 7.8017.825 (q, 1H, ArH), 10.818 (s, 1H, ArOH); MS m/z (%): 39 (7), 51 (5), 65 (13), 77 (3), 91 (54), 117 (41), 118 (100), 119 (11), 120 (14), 121 (15), 256 (M+ 8). 2.2.3.2 3-Phenylpropyl 2-chlorobenzoate (2c). The compound was obtained in 82.6% yield as a brightyellow oil; 1 H NMR (400 MHz) : 2.105 (m, 2H, CH2 ), 2.799 (t, 2H, CH2 ), 4.365 (t, 2H, CH2 ), 7.1827.301 (m, 5H, ArH), 7.335 (m, 1H, ArH), 7.791 (q, 1H, ArH); MS m/z (%): 51 (3), 91 (18), 111 (11), 117 (64), 118 (100), 139 (17), 274 (M+ 8). 2.2.3.3 3-Phenylpropyl 2-bromobenzoate (2d). The compound was obtained in 81.5% yield as a yellow oil; 1 H NMR (400 MHz) : 2.102 (m, 2H, CH2 ), 2.796 (t, 2H, CH2 ), 4.362 (t, 2H, CH2 ), 7.1787.378 (m, 7H, ArH), 7.664 (m, 1H, ArH), 7.746 (q, 1H, ArH); MS m/z (%): 50 (3), 65 (4), 76 (6), 91 (17), 105 (2), 118 (100), 155 (4), 182 (7), 318 (M+ 1). 2.2.3.4 3-Phenylpropyl 2-ethoxybenzoate (2e). The compound was obtained in 55.1% yield as an orange oil; 1 H NMR (400 MHz) : 1.459 (t, CH3 , 3H),
930

2.103 (m, 2H, CH2 ), 2.801 (t, 2H, CH2 ), 4.129 (q, 2H, CH2 ), 4.326 (t, 2H, CH2 ), 6.9496.990 (m, 2H, ArH), 7.1667.319 (m, 5H, ArH), 7.4197.463 (m, 1H, ArH), 7.773 (q, 1H, JH = 1.6 Hz, JH = 9.6 Hz, ArH); MS m/z (%): 51 (2), 65 (12), 77 (4), 91 (28), 103 (2), 118 (100), 133 (4), 49 (11), 166 (6), 284 (M+ 6). 2.2.3.5 3-Phenylpropyl 2,4-dihydroxybenzoate (2f). The compound was obtained in 74.8% yield as an orange oil; 1 H NMR (400 MHz) : 2.097 (m, 2H, CH2 ), 2.775 (t, 2H, CH2 ), 4.324 (t, 2H, CH2 ), 6.254 (s, 1H, ArH), 6.3666.411 (m, 2H, ArH), 7.1837.324 (m, 5H, ArH), 7.707 (d, 1H, ArH), 10.082 (s, 1H, ArOH); MS m/z (%): 53 (4), 65 (6), 81 (5), 91 (48), 108 (6), 118 (100), 137 (18), 272 (M+ 10). 2.2.3.6 3-Phenylpropyl 5-chloro-2-hydroxybenzoate (2g). The compound was obtained in 55.1% yield as an orange oil; 1 H NMR (400 MHz) : 2.161 (m, 2H, CH2 ), 2.789 (t, 2H, CH2 ), 4.326 (t, 2H, CH2 ), 6.930 (d, 1H, ArH), 7.1597.325 (m, 5H, ArH), 7.390 (d, 1H, ArH), 7.636 (d, 1H, ArH), 11.032 (s, 1H, ArH); MS m/z (%): 51 (3), 65 (7), 77 (4), 91 (81), 118 (100), 154 (13), 290 (M+ 7). 2.2.3.7 3-Phenylpropyl 2-methoxybenzoate (2h). The compound was obtained in 61.5% yield as a paleyellow-green oil; 1 H NMR (400 MHz) : 2.078 (m, 2H, CH2 ), 2.794 (t, 2H, CH2 ), 3.937 (d, 3H, ArOCH3 ), 4.320 (t, 2H, CH2 ), 6.892 (m, 2H, ArH), 7.1777.310 (m, 5H, ArH), 7.469 (m, 1H, ArH), 7.782 (q, 1H, ArH); MS m/z (%): 51 (4), 65 (5), 77 (21), 91 (15), 105 (4), 118 (100), 135 (35), 270 (M+ 3). 2.3.3.8 3-Phenylpropyl 4-methoxybenzoate (2i). The compound was obtained in 55.1% yield as an orange oil; 1 H NMR (400 MHz) : 2.112 (m, 2H, CH2 ), 2.777 (t, 2H, CH2 ), 3.852 (d, 3H, ArOCH3 ), 4.306 (t, 2H, CH2 ), 6.8966.933 (m, 2H, ArH), 7.1567.309 (m, 5H, ArH), 7.9688.005 (m, 2H, ArH); MS m/z (%): 51 (2), 65 (4), 77 (13), 91 (12), 107 (6), 118 (100), 135 (29), 152 (11), 270 (M+ 2). 2.3.3.9 3-Phenylpropyl 3,4,5-trimethoxybenzoate (2j). The compound was obtained in 34.9% yield as a pale-yellow solid; 1 H NMR (400 MHz) : 2.094 (m, 2H, CH2 ), 2.759 (t, 2H, CH2 ), 3.8793.924 (m, 9H, ArOCH3 ), 4.340 (t, 2H, CH2 ), 7.1597.297 (m, 7H, ArH); MS m/z (%): 53 (3), 65 (4), 77 (5), 91 (18), 117 (22), 118 (15), 137 (3), 195 (12), 197 (22), 212 (100), 330 (M+ 21). 2.3.3.10 3-Phenylpropyl 2-hydroxy-4-methoxybenzoate (2k). The compound was obtained in 61.5% yield as a pale-yellow-green oil; 1 H NMR (400 MHz) : 2.106 (m, 2H, CH2 ), 2.781 (t, 2H, CH2 ), 3.819 (d,
Pest Manag Sci 63:928934 (2007) DOI: 10.1002/ps

Insecticidal activity of daphneolone analogues

3H, ArOCH3 ), 4.326 (t, 2H, CH2 ), 6.450 ArH), 7.1647.316 (m, 5H, ArH), 7.718 JH = 8.4 Hz, ArH), 11.032 (s, 1H, ArH); (%): 51 (5), 65 (10), 79 (6), 91 (66), 107 (100), 150 (55), 168 (39), 286 (M+ 13).

(m, (m, MS (6),

2H, 1H, m/z 118

values were corrected for control mortality by Abbotts formula.20 The software SPSS 13.0 for Windows 2004 was used for linear regression of probit mortality on logarithmic concentration to obtain LC50 values.

2.3.3.11 3-Phenylpropyl 3, 4-dimethoxybenzoate (2l). The compound was obtained in 55.1% yield as an orange oil; 1 H NMR (400 MHz) : 2.105 (m, 2H, CH2 ), 2.785 (t, 2H, CH2 ), 3.941 (d, 6H, ArOCH3 ), 4.326 (t, 2H, CH2 ), 6.893 (d, 1H, ArH), 7.1787.317 (m, 5H, ArH), 7.553 (d, 1H, JH = 2.0 Hz, ArH), 7.677 (q, 1H, JH = 2.4 Hz, JH = 8.8 Hz, ArH); MS m/z (%): 51 (3), 65 (4), 77 (9), 91 (13), 107 (3), 117 (28), 137 (5), 165 (16), 182 (100), 300 (M+ 15). 2.3.3.12 3-Phenylpropyl nicotinate (2m). The compound was obtained in 52.1% yield as a colourless oil; 1 H NMR (400 MHz) : 2.105 (m, 2H, CH2 ), 2.793 (t, 2H, CH2 ), 4.365 (t, 2H, CH2 ), 7.1837.317 (m, 5H, ArH), 7.388 (m, 1H, PyH), 8.255 (m, 1H, PyH), 8.765 (q, 1H, PyH), 9.204 (d, 1H, PyH,); MS m/z (%): 51 (15), 65 (7), 77 (6), 78 (26), 79 (5), 91 (28), 103 (4), 106 (15), 115 (5), 117 (86), 118 (100), 119 (9), 137 (15), 241 (M+ 2). 2.3.3.13 3-Phenylpropyl furan-2-carboxylate (2n). The compound was obtained in 81.4% yield as an orange oil; 1 H NMR (400 MHz) : 2.096 (m, 2H, CH2 ), 2.773 (t, 2H, CH2 ), 4.342 (t, 2H, CH2 ), 6.505 (m, 1H, FuH), 7.159 (t, 1H, FuH), 7.1677.306 (m, 5H, ArH), 7.576 (t, 1H, FuH); MS m/z (%): 51 (3), 65 (6), 77 (4), 91 (25), 95 (25), 103 (3), 118 (100), 230 (M+ 1). 2.3 Biological assay The aphid colony was reared on cotton plants in the greenhouse. They were maintained at 2223 C with a 14:10 h light:dark photoperiod. Vigorous and apterous aphids (four-day-old aphids) were used in the experiments. To obtain four-day-old aphids, adult cotton aphids were transferred to cotton plants and allowed to deposit nymphs overnight, and then the adult aphids were removed. Four days later, these aphids were collected for the bioassays. The test method was adapted from Zongbing Zhang.19 Bioassays were carried out at room temperature (2021 C) in petri dishes (15 cm diameter). Solutions of the test products and omethoate (standard) were separately prepared in acetone to give nal compound concentrations ranging from 0.04 to 90 g L1 , and fresh cotton leaves were immersed in the solutions and allowed to air dry in petri dishes. Healthy and apterous aphids were gently dislodged from the undersides of leaves onto the treated leaves. Each bioassay used 50 aphids, and the entire experiment was replicated 3 times. The control leaves were treated only with the solvent. The number of dead aphids was recorded after 48 h to calculate the mortality rate (%). Mortality
Pest Manag Sci 63:928934 (2007) DOI: 10.1002/ps

3 RESULTS AND DISCUSSION 3.1 Synthesis The esterication of carboxylic acids with alcohols is a type of classical reaction. Because hydrolysis of the ester occurs at the same time, the yield is hard to improve. Recently, some catalysts such as iodine, 2,2-dimethoxypropane/TMSCl, CBr4/hv and diphenyl ammonium triate21 23 have been developed to improve the yield. The present authors used concentrated sulfuric acid as the catalyst to prepare 3-phenylpropyl benzoates in view of the fact that it is an inexpensive and convenient reagent and the title compounds can be easily prepared in good yield. 3.2 Insecticidal activity The LC50 values of the title compounds against cotton aphids are shown in Tables 1 and 2, and corrected mortalities in Table 3. The corresponding data for the reference compounds are shown in Tables 4 and 5. Modications on the phenyl ring of compound 1, while not leading to complete inactivation, showed a tendency to reduce activity (1a1e, Table 1). The furan ring has been recognized as being sterically similar to the benzene ring. However, compound 1f (R = 2-furan) did not show the expected activity. The insecticidal activities of analogues of compound 2 are shown in Tables 2 and 3. Firstly, the methoxy group was used as a probe, and compounds 2h2l were synthesized. Although their activity did not reach the level of compound 2 (Table 4), the insecticidal activity of compound 2h (R = 2-OCH3 C6 H4 ) was the best among these compounds. Furthermore, the larger the number of substituents, the weaker was the insecticidal activity of the compound. In the next step, ortho-methoxy was exchanged for other substituents. For these compounds substituted at the ortho position, the order of activity was 2c (R = 2-ClC6 H4 ) > 2d (R = 2-BrC6 H4 ) > 2h (R = (R = 2-OC2 H5 C6 H4 ) > 2-OCH3 C6 H4 ) > 2e
Table 1. Insecticidal activity of title compounds 1a1f

R O

H N

Compound
1a 1b 1c 1d 1e 1f

R 2-OHC6 H4 2-BrC6 H4 2-OCH3 C6 H4 2-OC2 H5 C6 H4 2-ClC6 H4 2-C4 H4 O

Slope 0.52 0.83 0.87 0.78 0.53 0.92

LC50 (g L1 ) 154.15 138.04 39.55 57.91 239.08 24.79

95% ducial limits (g L1 ) 53.15451.15 45.13257.64 24.5676.12 31.01106.79 91.68343.11 22.9348.52

931

L Chen et al.
Table 2. Insecticidal activity of title compounds 2a2n

O R O

Compound
2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m 2n

R 4-ClC6 H4 2-OHC6 H4 2-ClC6 H4 2-BrC6 H4 2-OC2 H5 C6 H4 2,4-(OH)2 C6 H3 2-OH-5-Cl C6 H3 2-OCH3 C6 H4 4-OCH3 C6 H4 3,4,5-(OCH3 )3 C6 H2 2-OH-4-OCH3 C6 H3 3,4-(OCH3 )2 C6 H3 3-C5 H4 N 2-C4 H4 O

Slope 0.75 0.41 1.04 1.06 1.02 0.75 0.62 0.28 0.67 0.51 0.84 0.75 0.66 0.95

LC50 (g L1 ) 4.19 95.88 20.47 26.84 65.81 22.58 73.62 31.38 51.07 336.56 63.69 157.62 11.29 0.85

95% ducial limits (g L1 ) 2.397.26 55.31164.88 9.1445.60 10.6767.89 36.41119.87 12.9738.65 42.94127.98 17.9855.59 30.9485.02 211.91541.80 33.24119.26 99.12253.42 6.1820.36 0.511.42

Table 3. Corrected mortality of title compounds 1a1f and 2a2n

Corrected mortality (%)a at concentration (g L1 ) Compound

1a 1b 1c 1d 1e 1f 2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k 2l 2m 2n
a b

R 2-OHC6 H4 2-BrC6 H4 2-OCH3 C6 H4 2-OC2 H5 C6 H4 2-ClC6 H4 2-C4 H4 O 4-ClC6 H4 2-OHC6 H4 2-ClC6 H4 2-BrC6 H4 2-OC2 H5 C6 H4 2,4-(OH)2 C6 H3 2-OH-5-Cl C6 H3 2-OCH3 C6 H4 4-OCH3 C6 H4 3,4,5-(OCH3 )3 C6 H2 2-OH-4-OCH3 C6 H3 3,4-(OCH3 )2 C6 H3 3-C5 H4 N 2-C4 H4 O

90 47.3 44.7 62.0 55.3 41.3 69.3 84.7 50.0 76.0 70.7 55.3 69.3 52.0 54.0 54.7 38.7 56.0 44.0 72.7 98.7

30 35.3 28.7 48.0 42.7 30.7 54.0 71.3 44.0 56.0 53.3 37.3 50.0 38.7 49.3 44.0 31.3 37.3 29.3 60.0 92.0

10 25.3 16.7 28.7 26.0 24.0 34.0 62.0 32.0 36.7 32.7 19.3 40.0 32.0 44.0 34.0 20.0 25.3 18.0 49.3 84.7

3.33 19.3 8.7 16.0 17.3 17.3 23.3 47.3 26.0 20.0 16.0 8.7 28.7 20.0 39.3 22.0 14.7 14.7 9.3 34.0 71.3

1.11 12.7 4.7 8.7 9.3 10.7 10.0 36.7 20.0 9.3 6.0 4.0 15.3 14.0 36.7 14.0 10.6 6.7 5.3 28.0 52.7

0.37 8.0 NTb 4.7 4.0 6.7 4.7 20.0 17.3 4.0 3.3 NT 9.3 6.7 32.0 6.0 6.0 NT 3.3 16.7 36.7

0.12 6.0 NT NT NT NT NT 11.3 12.0 NT NT NT 4.0 NT 25.3 4.0 4.7 NT NT 10.7 20.7

0.04 4.0 NT NT NT NT NT 6.7 8.0 NT NT NT NT NT 18.0 NT NT NT NT 4.0 11.3

Based on the average of three replications; control mortality was below 1%. NT = not tested.

Table 4. Insecticidal activity of reference compounds

O N H 1

O O

Compound
1 2 a b

Slope 1.36 0.44 2.5 2.6 1.37

LC50 (g L1 ) 11.51 1.18 0.47 0.23 0.28

95% ducial limits (g L1 ) 6.0821.70 0.652.13 0.400.50 0.200.24 0.160.51

Omethoate
932

2b (R = 2-OHC6 H4 ). Although their performance was still poor, the two compounds (2c and 2d) substituted with halogen were more active than the other compounds. Interestingly, when a chlorine atom was incorporated at the para position of the benzoic acid phenyl ring, compound 2a (R = 4-ClC6 H4 ) showed activity close to that of compound 2 (LC50 ratio = 0.3). The result demonstrated that electron-withdrawing substituents at the ortho position were favourable to biological activity. However, the substitution of a hydroxyl group at the ortho position on the phenyl ring reduced or completely eliminated
Pest Manag Sci 63:928934 (2007) DOI: 10.1002/ps

Insecticidal activity of daphneolone analogues

Table 5. Corrected mortality of reference compounds

Corrected mortality (%)a at concentration (g L1 ) Compound

1 2 a b

90.00 90.0 79.3 NT NT NT

30.00 71.3 70.0 100 100 100

10.00 45.3 66.7 100 100 98.0

3.33 22.7 60.7 98.7 100 91.3

1.11 7.3 50.7 82.7 96.0 80.0

0.37 3.3 42.0 39.3 71.3 59.3

0.12 NTb 34.0 7.3 22.7 30.0

0.04 NT 23.3 NT 2.7 11.3

Omethoate
a b

Based on the average of three replications; control mortality was below 1%. NT = not tested.

activity, possibly because the hydroxyl group was associated with a carbonyl group. For synthetic reasons, only two 2,4-disubstituted analogues were prepared, both containing the 2hydroxy substituent. Compound 2f [R = 2, 4 (OH)2 C6 H3 ] was superior to compound 2k (R = 2-OH-4-OCH3 C6 H3 ). This indicated that the substituent on the para position should not be an electrondonating group. In addition, compound 2g (R = 2-OH-5-ClC6 H3 ) exhibited higher insecticidal activity than compound 2b (R = 2-OHC6 H4 ). The above result indicated that the incorporation of halogens at the para position of the benzoic acid phenyl ring was feasible. Unfortunately, synthetic difculties precluded an extensive survey of substituents with halogen. Further work included heterocycle substitution of the benzoic acid phenyl ring, and compounds 2n (R = 2-furan) and 2m (R = 3-pyridine) were synthesized. According to the LC50 values (Table 2), compound 2n showed the best activity against the aphids, and its performance was clearly superior to that of compound 2. The biological assay of the analogues of compound 2 can be summarized as follows: (a) a substituent introduced into the para position of the phenyl ring should not be an electron-donating group; (b) electron-withdrawing substituents at the ortho position were favourable to biological activity; (c) incorporation of halogens at the para position of the benzoic acid phenyl ring was feasible; (d) substitution of furan for the phenyl ring was favourable. It is well known that structural modications to the lead compounds obtained from plants may result in novel environmentally benign insecticides with high activity. The insecticidal properties of 1,5-diphenyl1-pentanone and 1,5-diphenyl-2-penten-1-one, which were extracted from S. chamaejasme, were reported in 2001. To the authors knowledge, however, structural modications carried out on these botanical aphicides isolated from S. chamaejasme have not been reported previously. In addition, bioisosterism16 is a rational approach in drug design. Thus, the present authors have synthesized a series of novel compounds and discussed the structureactivity relationships for selected substitution patterns.
Pest Manag Sci 63:928934 (2007) DOI: 10.1002/ps

Another aim in this work was to evaluate the insecticidal activity of each compound, and to nd out whether the structural modication carried out on lead compounds would result in a synthetic product more active than the natural product. In comparison with lead compounds a and b, the compounds described here showed low insecticidal activity. Insecticidal assays indicated that any substitution on the phenyl ring reduced the activity. However, the furan derivative 2n showed higher activity. In addition, it is interesting to note that the analogues of compound 2 showed somewhat better activity than the analogues of compound 1. Thus, the modication of compound 2n is of some promise, and highly active analogues are expected to be found by further work. In conclusion, a series of novel compounds has been synthesised and assayed for insecticidal activity against cotton aphids, and structureactivity relationships have been elucidated in this study. Compound 2n (3-phenylpropyl furan-2-carboxylate) shows excellent activity and has therefore been selected as the lead compound for further studies.

ACKNOWLEDGEMENTS This project was supported by the National Natural Science Foundation of China (20372052 and 20572076) and the Hi-Tech Research and Development of China (2006AA10A209). The authors are very grateful to Shixin Yang, Ke Tao and Hong Jin for their assistance with the manuscript.

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Pest Manag Sci 63:928934 (2007) DOI: 10.1002/ps