Design, synthesis and evaluation of insecticidal activity of phenylthiazole derivative containing primary amide and cyanogroup
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摘要:目的
噻唑是一类具有广泛生物活性的五元杂环化合物，本文设计并合成一系列含有伯酰胺及氰基的苯基噻唑衍生物，进一步挖掘噻唑骨架在防治鳞翅目害虫领域的潜力。
方法以不同取代基的苯甲酸为原料合成含有伯酰胺及氰基的噻唑衍生物，并经1H NMR、13C NMR和ESI-MS确证结构。采用浸液法测定目标化合物对小菜蛾Plutella xylostella的生物活性，并通过密度泛函理论(Density functional theory，DFT)计算从分子轨道层面解释该骨架具有杀虫活性的原因和差异。
结果经结构确证，合成了22个含有伯酰胺及氰基的噻唑衍生物，其中6个化合物(6d、7d、13a、13b、14a和14b)对小菜蛾表现出很好的杀虫活性(校正死亡率 > 50%)，尤其是化合物6d和7d，对小菜蛾的LC50达到了23.94和30.37 mg/L。构效关系表明，苯环仅取代4−CF3且5−位噻唑未取代时，表现出最优的杀虫活性。DFT计算结果表明，4−三氟甲基苯基噻唑既传递电子又接受电子，且化合物6d比7d具有更小的HOMO−LUMO间隙(ΔE)。
结论化合物6d可作为先导化合物进一步开发，本研究可为含有噻唑骨架杀虫剂的分子设计与优化提供有价值的线索。
Abstract:ObjectiveThiazole is a class of five-membered heterocyclic compounds with a wide range of biological activities, which are widely used in the fields of medicine and agrochemicals. In this paper, we designed and synthesized a series of phenyl thiazole derivatives containing primary amide and cyanogroup to further explore the potential of thiazole scaffold in controlling Lepidoptera pests.
MethodThe new thiazole derivatives containing primary amide and cyanogroup were synthesized from benzoic acid with different substituent, and the structures were confirmed by 1H NMR, 13C NMR and ESI-MS. The biological activities of target products against Plutella xylostella were determined by the leaf immersion method. The density functional theory (DFT) calculation was used to explain the reason and difference of insecticidal activity of this skeleton at the molecular orbital level.
ResultThe results of structural verification showed 22 thiazole derivatives containing primary amide and cyanogroup were synthesized. Six compounds (6d, 7d, 13a, 13b, 14a and 14b) showed good insecticidal activities (mortality > 50%) against P. xylostella, especially the compounds of 6d and 7d with LC50 of 23.94 and 30.37 mg/L respectively. The structure-activity relationship showed the optimal insecticidal activity was demonstrated for benzene ring monosubstituted 4-CF3 and 5-position thiazole unsubstituted. The results of DFT calculation showed that [4-(trifluoromethyl) phenyl] thiazole both delivered and received electrons, and the compound 6d has a smaller HOMO−LUMO gap (ΔE) than 7d.
ConclusionThe compound 6d can be further developed as a lead compound. This research provides a valuable clue for molecule design and optimization of insecticide containing thiazole scaffold.
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图 1 目标化合物6a~6i和7a~7i的合成路线
Figure 1. The synthetic routes of target compounds of 6a~6i and 7a~7i
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图 2 目标化合物13a、13b、14a和14b的合成路线
Figure 2. The synthetic routes of the target compounds of 13a, 13b, 14a and 14b
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图 4 化合物6d、7d、13a、13b、14a和14b的前沿分子轨道
红色部分代表正分子轨道，绿色部分代表负分子轨道
Figure 4. Frontier molecular orbitals of the compounds of 6d, 7d, 13a, 13b, 14a and 14b
The red part represented positive molecular orbital and the green part represented negative molecular orbital
表 1 目标化合物处理小菜蛾3龄幼虫48 h后的死亡率1)
Table 1 The mortality rate of the 3rd-instar larvae of Plutella xylostella treated by target compound after 48 hours
化合物
Compound校正死亡率/%
Corrected
mortality rate化合物
Compound校正死亡率/%
Corrected
mortality rate6a 6.67 ± 3.33ab 7a 0.00 ± 0.00a 6b 35.56 ± 2.22d 7b 9.44 ± 0.56b 6c 13.33 ± 3.33b 7c 0.00 ± 0.00a 6d 100.00 ± 0.00g 7d 100.00 ± 0.00g 6e 0.00 ± 0.00a 7e 0.00 ± 0.00a 6f 27.27 ± 0.00c 7f 28.33 ± 1.67cd 6g 13.33 ± 6.67b 7g 0.00 ± 0.00a 6h 0.00 ± 0.00a 7h 0.00 ± 0.00a 6i 0.00 ± 0.00a 7i 0.00 ± 0.00a 13a 62.78 ± 3.64f 14a 51.52 ± 1.52e 13b 69.44 ± 6.26f 14b 53.33 ± 4.24e 茚虫威
Indoxacarb100.00 ± 0.00g 1) 表中数据为平均值±标准误；同列数据后的不同字母表示差异显著(P < 0.05，Duncan’s法)
1) The data in the table was mean ± standard error, the different lowercase letters in the same column indicated significant difference (P<0.05, Duncan’s method)
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表 2 化合物6d和7d处理小菜蛾3龄幼虫48 h后的杀虫活性
Table 2 Insecticidal activities of compounds 6d and 7d against the 3rd-instar larvae of Plutella xylostella at 48 hours after treatment
化合物
CompoundLC50/
(mg·L−1)95%置信区间/
(mg·L−1)
95% confidence
interval斜率±标准误
Slop ± SEχ2 6d 23.94 19.94~28.75 3.67 ± 0.47 3.102 7d 30.37 25.18~36.90 3.41 ± 0.44 4.017 茚虫威
Indoxacarb4.22 3.08~5.53 1.92 ± 0.30 1.650
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