Design, synthesis and biological activities of novel diamide derivatives containing bioactive cyclopropanecarboxylic acid fragments
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摘要: 为探索具有新颖结构的杀虫剂先导，将多种含环丙甲酸的活性片段引入二酰胺类杀虫剂，设计并合成了21个新型的二酰胺类衍生物，其结构均经过核磁共振波谱 (NMR)及高分辨质谱 (HRMS)表征。测试了所有目标衍生物对苜蓿蚜Aphis craccivora、东方黏虫Mythimna separate、小麦赤霉病菌Fusarium graminearum及小麦白粉病菌Blumeria graminis的生物活性。结果显示：大部分邻位二酰胺类衍生物的对两种供试病原菌的杀菌活性不够理想，而对两种害虫靶标均有良好的杀虫活性。在500 mg/L质量浓度下，衍生物 10h 对苜蓿蚜的致死率为90%， 10k 对东方黏虫的致死率达100%，这两个衍生物均可作为潜在的杀虫先导衍生物加以进一步研究。Abstract: In order to discover insecticide leads with novel structures, a variety of cyclopropanecarboxylic acid-containing active fragments were introduced into diamide insecticides. 21 novel diamide derivatives were designed and synthesized. Their structures were characterized by nuclear magnetic resonance spectroscopy (NMR) and high resolution mass spectrometry (HRMS). And their biological activities against Aphis craccivora, Mythimna separate, Fusarium graminearum and Blumeria graminis were evaluated. The results suggestted that most of our anthranilic diamides had low fungicidal activities on the two fungi and good insecticidal activities against the two insect targets. And at the concentration of 500 mg/L, 10h exhibited a mortality rate of 90% against A. craccivora, while 10k possessed a rate of 100% against M. separate. Both two derivatives could be further optimized as potential insecticide leads.
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Key words:
- cyclopropanecarboxylic acid /
- bioactive fragment /
- diamide /
- insecticidal acticity
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2 含环丙甲酸片段的天然产物、药物及农药
2. Natural products, drugs and pesticides containing cyclopropanecarboxylic acid fragments
表 1 500 mg/L下8a~8c、9a~9c和10a~10c对4种靶标的杀虫或杀菌活性
Table 1. The insecticidal or fungicidal activities against 4 targets of 8a-8c, 9a-9c and 10a-10c at 500 mg/L
衍生物
Derative结构通式
General structureR1 死亡率c
Mortality ratec/%抑制率
Inhibitory rate/%苜蓿蚜
A. craccivora东方黏虫
M. separate小麦赤霉病菌
F. graminearum小麦白粉病菌
B. graminis8a 
20 15 10 0 8b a 
50 0 15 5 8c 
20 5 5 0 9a 
0 0 40 0 9b a 
35 10 35 20 9c 
25 30 30 50 10a 
20 65 15 0 10b a 
60 25 35 0 10c 
25 45 20 0 高效氯氟氰菊酯b lambda-cyhalothrin b 100 氯虫苯甲酰胺b chlorantraniliprole b 100 氰烯菌酯b phenamacril b 100 戊唑醇b tebuconazole b 100 注：a 衍生物为消旋体，此处结构式为相对构型。b 作为阳性对照的氯虫苯甲酰胺、高效氯氟氰菊酯、氰烯菌酯和戊唑醇测试浓度均为100 mg/L。c 对两种害虫靶标的空白对照的死亡率为0。Note: a The derivitives were racemic, and relative configurations were shown. b Chlorantraniliprole, lambda-cyhalothrin, phenamacril and tebuconazole were tested at 100 mg/L. c The mortality rate of blank control were both zero for the 2 insect targets. 
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表 2 10d~10o对4种靶标的杀虫或杀菌活性
Table 2. The insecticidal and fungicidal activities against 4 targets of 10d-10o
衍生物
Deriv.R1 含该活性片段的
代表性药物或农药
Representative drug
or pesticide containing
this bioactive fragment质量浓度
Conc./
(mg/L)致死率b
Mortalityb/%抑制率
Inhibitory rate/%苜蓿蚜
A. craccivora东方黏虫
M. separate小麦赤霉病菌
F. graminearum小麦白粉病菌
B. graminis10d a 
西司他丁 cilastatin 500 25 30 5 0 10e 
甲氰菊酯 fenpropathrin 500 10 15 20 5 10f a 
胺菊酯 tetramethrin 500 70 20 30 10 10g a 
氯菊酯 permethrin 500 75 25 20 5 10h a 
高效氯氟氰菊酯 lambda-cyhalothrin 500 90 40 15 0 200 55 10i a 
氟氯苯菊酯 bayticol 500 65 30 35 15 10j 
RO5444101 500 15 40 10 0 10k 
RO5459072 [22] 500 10 100 15 0 200 70 10l 
VH298 [23] 500 10 80 5 0 200 20 10m 
VZ185 [24] 500 25 35 25 15 10n 
鲁玛卡托 lumacaftor 500 15 65 35 10 10o a 
仑布雷生 lemborexant 500 30 40 45 20 高效氯氟氰菊酯 lambda-cyhalothrin 100 100 氯虫苯甲酰胺 chlorantraniliprole 100 100 氰烯菌酯 phenamacril 100 100 戊唑醇 tebuconazole 100 100 注：a衍生物为消旋体，此处结构式为相对构型。b对两害虫靶标的空白对照的死亡率为0。Note: a The derivitives were racemic and relative configurations were shown. b The mortality rate of blank control were both zero for the 2 insect targets.
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[1] PINKERTON A B, LEE T T, HOFFMAN T Z, et al. Synthesis and SAR of thiophene containing kinesin spindle protein (KSP) inhibitors[J]. Bioorg Med Chem Lett, 2007, 17(13): 3562-569. doi: 10.1016/j.bmcl.2007.04.076 [2] MAGESH S, SAVITA V, MORIYA S, et al. Human sialidase inhibitors: design, synthesis, and biological evaluation of 4-acetamido-5-acylamido-2-fluoro benzoic acids[J]. Bioorg Med Chem, 2009, 17(13): 4595-4603. doi: 10.1016/j.bmc.2009.04.065 [3] HAQUE T S, TADESSE S, MARCINKEVICIENE J, et al. Parallel synthesis of potent, pyrazole-based inhibitors of Hlicobacter pylori dihydroorotate dehydrogenase[J]. J Med Chem, 2002, 45(21): 4669-4678. doi: 10.1021/jm020112w [4] THOMSON S A, BANKER P, BICKETT D M, et al. Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy[J]. Bioorg Med Chem Lett, 2009, 19(4): 1177-1182. doi: 10.1016/j.bmcl.2008.12.085 [5] YANG J, ZHAO Y T, WAN J, et al. Synthesis and biological evaluation of novel benodanil-heterocyclic carboxamide hybrids as a potential succinate dehydrogenase inhibitors[J]. Molecules, 2020, 25(18): 4291. doi: 10.3390/molecules25184291 [6] 许庆博, 梁培博, 路慧哲, 等. 含双酰胺结构的氟吡菌酰胺衍生物的设计、合成及生物活性研究[J]. 有机化学, 2021, 41(8): 3116-3125.XU Q B, LIANG P B, LU H Z, et al. Design, synthesis and bioactivity of fluopyram derivatives containing diamide moiety[J]. Chin J Org Chem, 2021, 41(8): 3116-3125. [7] LAHM G P, SELBY T P, FREUDENBERGER J H, et al. Insecticidal anthranilic diamides: a new class of potent ryanodine receptor activators[J]. Bioorg Med Chem Lett, 2005, 15(22): 4898-4906. doi: 10.1016/j.bmcl.2005.08.034 [8] KATSUTA H, NOMURA M, WAKITA T, et al. Discovery of broflanilide, a novel insecticide[J]. J Pestic Sci, 2019, 44(2): 120-128. doi: 10.1584/jpestics.D18-088 [9] ISAACS A K, QI S Z, SARPONG R, et al. Insect ryanodine receptor: distinct but coupled insecticide binding sites for [N-C3H3] chlorantraniliprole, flubendiamide, and [3H] ryanodine[J]. Chem Res Toxicol, 2012, 25(8): 1571-1573. doi: 10.1021/tx300326m [10] GAO Y, ZHANG Y, WU F, et al. Exploring the interaction mechanism of desmethyl-broflanilide in insect GABA receptors and screening potential antagonists by in silico simulations[J]. J Agric Food Chem, 2020, 68(50): 14768-14780. doi: 10.1021/acs.jafc.0c05728 [11] FAN Y Y, GAO X H, YUE J M. Attractive natural products with strained cyclopropane and/or cyclobutane ring systems[J]. Sci China Chem, 2016, 59(9): 1126-1141. doi: 10.1007/s11426-016-0233-1 [12] TALELE T T. The “cyclopropyl fragment” is a versatile player that frequently appears in preclinical/clinical drug molecules[J]. J Med Chem, 2016, 59(19): 8712-8756. doi: 10.1021/acs.jmedchem.6b00472 [13] LAMBERTH C. Small ring chemistry in crop protection[J]. Tetrahedron, 2019, 75(33): 4365 4383. [14] FIGUEIREDO J L, AIKAWA M, ZHENG C, et al. Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease[J]. Am J Pathol, 2015, 185(4): 1156-1166. doi: 10.1016/j.ajpath.2014.11.026 [15] ZHOU M W, HU Y M, EN K, et al. Efficient cyclopropanation of aryl/heteroaryl acetates and acetonitriles with vinyl diphenyl sulfonium triflate[J]. Tetrahedron Lett, 2018, 59(14): 1443-1445. doi: 10.1016/j.tetlet.2018.02.080 [16] KAGABU S, KURAHASHI Y. Carpropamid, a new fungicide for rice blast control[J]. J Pestic Sci, 1998, 23(2): 145-147. doi: 10.1584/jpestics.23.145 [17] GERSPACHER M, FURET P, PISSOT-SOLDERMANN C, et al. 2-Amino-aryl-7-aryl-benzoxazoles as potent, selective and orally available JAK2 inhibitors[J]. Bioorg Med Chem Lett, 2010, 20(5): 1724-1727. doi: 10.1016/j.bmcl.2010.01.069 [18] NAIK R, WON M, KIM B K, et al. Synthesis and structure–activity relationship of (E)-phenoxyacrylic amide derivatives as hypoxia-inducible factor (HIF) 1α inhibitors[J]. J Med Chem, 2012, 55(23): 10564-10571. doi: 10.1021/jm301419d [19] 农药室内生物测定试验准则 杀虫剂 第 14 部分: 浸叶法: NY/T 1154.14—2008[S]. 北京: 中国农业出版社, 2008.Guideline for laboratory bioassay of pesticides, part 14: leaf-dipping method: NY/T 1154.14—2008[S]. Beijing: China Agriculture Press, 2008. [20] 农药室内生物测定试验准则 杀菌剂 第9部分 抑制灰霉病菌实验 叶片法: NY/T 1156.9—2008[S]. 北京: 中国农业出版社, 2008.Guidelines for laboratory bioassay of pesticides. Part 9. detached leaf test for fungicide control Botrytis cinerea Pers. : NY/T 1156.9—2008 [S]. Beijing: China Agriculture Press, 2008. [21] 农药室内生物测定试验准则 杀菌剂 第4部分: 防治小麦白粉病试验 盆栽法: NY/T 1156.4—2006[S]. 北京: 中国农业出版社, 2006.Pesticides guidelines for laboratory bioactivity tests. Part 4. potted plant test for fungicide control of powdery mildew on wheat: NY/T 1156.4—2006 [S]. Beijing: China Agriculture Press, 2006. [22] HARGREAVES P, DAOUDLARIAN D, THERON M, et al. Differential effects of specific cathepsin S inhibition in biocompartments from patients with primary Sjögren syndrome[J]. Arthritis Res Ther, 2019, 21(1): 175. doi: 10.1186/s13075-019-1955-2 [23] GIRARDINI M, MANIACI C, HUGHES S J, et al. Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs[J]. Bioorg Med Chem, 2019, 27(12): 2466-2479. doi: 10.1016/j.bmc.2019.02.048 [24] ZOPPI V, HUGHES S J, MANIACI C, et al. Iterative design and optimization of initially inactive proteolysis targeting chimeras (PROTACs) identify VZ185 as a potent, fast, and selective von hippel-lindau (VHL) based dual degrader probe of BRD9 and BRD7[J]. J Med Chem, 2019, 62(2): 699-726. doi: 10.1021/acs.jmedchem.8b01413 -
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