Design, Synthesis, Biological Evaluation and SARs of Novel N-Substituted Sulfoximfnes as Potential Ryanodine Receptor Modulators

The sulfoximine group has been evaluated as a pharmacophore. Introducing the sulfoximine structure into medicinal compounds as exciting motifs has brought opportunities in drug discovery. In order to develop new ryanodine receptor （RyR） modulators, a series of phthalamides containing sulfoximine derivatives were designed, synthesized, and evaluated against oriental armyworm and diamondback moth for their insecticidal activities. These studies helped to elucidate the electronic and structural requirements around the sulfoximine motif for insecticidal activity. All new structures were synthesized and characterized by ^1H NMR, ^13C NMR, HRMS and bioassay and a preliminary structure-activity relationship （SAR） was discussed. The biological assessment indicated that most title compounds showed good to excellent larvicidal activities. Compounds la, le, and If gave excellent insecticidal activity against oriental armyworm, which showed 100% larvicidal activity at 0.5 mg/L. All compounds showed 100% larvicidal activity at 0.1 mg/L against diamondback moth. In particular, the larvicidal activities of le, If, and lh at 0.0001 mg/L were 50%, 20%, and 40%, respectively, reaching an activity as high as that of the commercial flubendiamide （40%, 0.0001mg/L）. Therefore, Ia, Ie, If and Ih could be considered as new lead structures for the development of new ryanodine receptor （RyR） modulators.

Synthesis, insecticidal activities and SAR studies of novel anthranilic diamides containing trifluoroethoxyl substituent and chiral amino acid moieties

Ryanodine receptors（RyRs） activator has become one class of popular insecticide because of its unique mode of action. In order to find more new RyRs activators as insecticidal agents, a series of 18 novel chiral anthranilic diamides were designed by introducing the D-alanine acid and D-serine acid esters as well as trifluoroethoxyl group into the anthranilic diamide skeleton and synthesized successfully based on anthranilic diamide and FKI-1033 structures. The structures of the title compounds Ia–i and IIa–i were confirmed by melting points,~1H NMR,^（13）C NMR, elemental analysis and specific optical rotation analysis.The preliminary bioassay results indicated that most of the title compounds exhibited considerable larvicidal activities against oriental armyworm at 10 mg/L, especially Ib, Ie and IIh showed remarkable insecticidal activities at 0.5 mg/L. The larvicidal activity against diamondback moth of Ia and IId were 80%and 90% respectively at 0.0001 mg/L, which was similar to that of chlorantraniliprole. The relationship between structure and insecticidal activity was analyzed to reveal a possible co-regulated effect of the chiral amino acid ester, halogen atom or cyano group, and trifluoroethyloxyl group of the skeleton structures of the title compounds, which will provide useful information for guiding the design and discovery of new RyRs activators and insecticidal agrochemicals.

鱼尼丁受体及以其为靶标的杀虫剂

作为最大的离子通道受体蛋白,鱼尼丁受体(Ry R)主要介导生物体胞内钙离子(Ca^(2+))释放而对肌肉兴奋-收缩耦联等生命活动起关键作用。由于在昆虫和脊椎动物体内存在显著差异,Ry R成为现代杀虫剂研发的理想靶标。由此开发的以氟苯虫酰胺和氯虫苯甲酰胺为代表的双酰胺类杀虫剂也成为最重要的杀虫剂品类之一。对Ry R及其Ca^(2+)释放通道的结构和功能进行介绍,并对以Ry R为靶标的杀虫剂(主要是双酰胺类杀虫剂)的研发背景与现状、化学合成、作用机制、生物活性、安全性、抗性、制剂及应用等进行总结,旨在为该类杀虫剂的研究、开发和应用提供指导。

Design,Synthesis,Biological Evaluation and SARs of Anthranilic Diamide Derivatives Containing Pyrrole Moieties

In order to find a new variety of ryanodine receptor(RyR)regulator with greater biological activity,a se-ries of anthranilic diamide derivatives possessing pyrrole structure was designed and synthesized in this study.The pyrrole derivatives were evaluated for their insecticidal activity against Mythimna separata and Plutella xylostella.As indicated by the preliminary biological activities,compounds 12h-12j and 121-12n exhibited a remarkable in-secticidal activity against M.separata at 0.25 mg/L.Compared to control chlorantraniliprole.compound 12i exhibited more excellent insecticidal activity at 0.1 mg/L.Meanwhile,compounds 12c,12h,12i.12j.121,and 12m were selected to test the insecticidal activity against P xylostella,which led to the desirable insecticidal activity at 1x103 mg/L.Notably,compound 121 demonstrated 47%insecticidal activity at 5×10^(-6) mg/L over the control.In addition,the biological mechanism of action of compound 12i was investigated by means of insect clectrophysiology experiment.

邻甲酰胺基苯甲酰胺类杀虫剂的研究进展

从结构划分的角度对邻甲酰胺基苯甲酰胺类鱼尼丁受体杀虫剂的研究情况进行了简要的综述。

Design, Synthesis, Structure-Activity Relationship and Insecticidal Activities of Trifluoromethyl-Containing Sulfiliminyl and Sulfoximinyl Phthalic Acid Diamide Structure

Due to a novel mode action,low toxicity to mammals and low residue characteristics,phthalic acid diamides have aroused considerable interests in agricultural chemistry.With introduction of N-cyano,N-trifluoroacetyl,N-carbamoylsulfiliminyl and sulfoximinyl substituents into phthalamides,12 novel derivatives containing trifluoromethyl moiety were designed and synthesized.All title compounds were characterized by ^(1)H NMR and high-resolution mass spectrometry.The preliminary results of biological activity assessment indicated that some title compounds exhibited moderate to good insecticidal activities against oriental armyworm(Pseudaletia separata Walker).In particular,Va gave higher activity against oriental armyworm and diamondback moth.The present work reported that the new trifluoromethylated diamides incorporating N-trifluoroacetylsulfoximinyl moieties are potential lead compounds for further structure optimization,providing some insight into the relating structure-activity relationship.

鱼尼丁受体杀虫剂Flubendiamine

本文介绍了鱼尼丁受体杀虫剂Flubendiamine的创制经纬、作用机制、生物活性、毒性及合成。

N-烷氧基邻氨基苯甲酰胺衍生物的合成与生物活性

为寻求高效、安全、经济杀虫活性化合物,设计并合成了12个N-烷氧基邻氨基苯甲酰胺衍生物,其结构经1H NMR、LC-MS、IR、元素分析确证。初步生物活性测定表明:该类化合物对粘虫、蚜虫、叶蝉和红蜘蛛具有显著的杀虫活性。

4种鱼尼丁受体类杀虫剂活性研究

采用叶片饲喂法,在处理后72 h,测定了4种鱼尼丁受体类杀虫剂对3种鳞翅目害虫(黏虫、甜菜夜蛾、小菜蛾)的活性,为其合理使用提供依据。试验结果表明:四氯虫酰胺和氯虫苯甲酰胺对3种鳞翅目幼虫的活性较高,均高于氟苯虫酰胺和溴氰虫酰胺的活性;4种鱼尼丁受体类杀虫剂对小菜蛾卵基本无活性;在不同亚致死剂量下,4种鱼尼丁受体类杀虫剂处理小菜蛾后,可使小菜蛾幼虫的体重降低,发育速度变缓。应用该类杀虫剂防治鳞翅目害虫的最佳时期应为卵孵化盛期至低龄幼虫活动期。不同亚致死剂量的4种鱼尼丁受体类杀虫剂处理小菜蛾后,均能对小菜蛾幼虫的正常生长产生影响。

新型邻甲酰氨基苯甲酰胺类杀虫剂四氯虫酰胺

四氯虫酰胺是以氯虫苯甲酰胺为先导开发而来的新型鱼尼汀受体变构调节剂,因而具有相似的化学结构、作用机理、杀虫谱和药效。四氯虫酰胺具有一定的生产成本优势,其市场潜力巨大,其开发情况值得关注。

Design,synthesis and insecticidal activities of novel anthranilic diamides containing polyfluoroalkyl pyrazole moiety

In order to discover new molecules with good insecticidal activities, a series of anthranilic diamides containing polyfluoroalkyl pyrazole were designed and synthesized, and their structures were characterized by1 H NMR and HRMS. Bioassays demonstrated that some of the title compound exhibited excellent insecticidal activities. The larvicidal activities of compound 8a, 8c, 8g, 8k and 8l against Mythimna separata Walker were 100% at 0.8 mg/L. The insecticidal activities of compound 8a, 8c,8e, 8g, 8k and 8l against Plutella xylostella Linnaeus were 100% at 0.4 mg/L. Surprisingly compounds 8a and 8c still showed 100% larvicidal activities against Plutella xylostella Linnaeus at 0.08 mg/L comparable to the commercialized Chlorantraniliprole. The LC_（50） of compound 8a and 8c against M. separata is 0.048 and 0.043 mg/L respectively.

The exploration of chiral N-cyano sulfiliminyl dicarboxamides on insecticidal activities

Due to new mechanism of action and ecofriendly characteristics,dicarboxamide insecticides have attracted more and more attentions in modern pest management.A series of 20 dual chiral N-cyano sulfilimines containing two centers（carbon and sulfur） were designed and synthesized.All title compounds were determined by ^1H NMR,high-resolution mass spectrometry（HRMS） and optical polarimeter.The preliminary results indicated that some of them exhibited favourable insecticidal activities against oriental armyworm（Pseudaletia separata Walker）.These isomers exhibited different impact on activity following the sequence as（Sc,Ss） 〉（Sc,Rs）,and the rule of title compounds＇ activity against oriental armyworm was 3-CF3≥2—CH3—4—Cl〉2,3,4-trifluro in the anilide moiety.The results indicated that these groups such as 3-CF3,2—CH3—4—Cl or 2,3,4-trifluro were inefficient to replace heptafluoroisopropyl group for high larvicidal activity,which provided some guidance for the further modifications of sulfiliminyl dicarboxamides.

Design, synthesis and insecticidal activities of novel 1-substituted-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives

A series of novel 5-（trifluoromethyl）-1H-pyrazole-4-carboxamide derivatives（6a–6n, 7a, 7b, and 8a-8f）were synthesised by placing the amide bond at the 4-position of the pyrazole ring. These derivatives differed from the structure of chlorantraniliprole analogues with the amide bond at the 5-position of the pyrazole ring. Preliminary bioassay results revealed that a few title compounds exhibited good insecticidal activities against lepidopteran pests, such as Plutella xylostella, Mythimna separate, Heliothis armigera, and Ostrinia nubilalis. Some title compounds also elicited broad-spectrum insecticidal activities against dipterous insects including Culex pipiens pallens after altering the amide position. Similar to pyrazole-5-carboxamide analogues, compounds 6b and 6e showed 100% insecticidal activity against P. xylostella, C. pipiens pallens, and M. separate at concentrations of 200, 2, and 200 mg/m L, respectively.This finding suggested that 5-（trifluoromethyl）-1H-pyrazole-4-carboxamide derivatives are potential alternative insecticides for management of agriculture pests.

Synthesis and Insecticidal Activities of Novel Phthalic Acid Diamides

In order to discover novel insecticides with the new action mode on ryanodine receptor （RyR）, a series of novel phthalic acid diamide derivatives were designed and synthesized. All compounds were characterized by 1H NMR spectra and HRMS. The preliminary results of biological activity assessment indicated that some title compounds exhibited excellent insecticidal activities against Mythimna separata, Spodoptera exigua, and Plutella xylostella. The title compound 3-nitro-N-cyclopropyl-N＇-[2-methyl-4-（perfluoropropan-2-yl）phenyl]phthalamidte （4a） was more efficient against diamondback moths than the control （chlorantraniliprole）. The effects of some title compounds on intracellular calcium of neurons from the Spodoptera exigua proved that the title compounds were RyR activators.

含吡唑杂环二酰胺类化合物的合成与杀虫活性研究

通过活性亚结构拼接,合成16个含吡唑杂环的新型二酰胺类化合物,其结构通过了IR,1H NMR和HRMS的表征,其中目标化合物3h的结构经X单晶衍射进一步确认.初步生测结果表明在500 mg/L浓度下,部分化合物对粘虫和苜蓿蚜有致死活性;在100 mg/L浓度下部分化合物对茶尺蠖幼虫具有致死活性,其中毒症状表现为拒食.

Design, Synthesis and Biological Activities of Novel Anthranilic Diamide Insecticide Containing Trifluoroethyl Ether

Two series of novel anthranilic diamide insecticide containing trifluoroethyl ether were designed and synthesized, and their structures were characterized by 1H NMR spectroscopy, elemental analysis and single crystal X-ray diffraction analysis. The insecticidal activities of the new compounds were evaluated. The results of bioassays indicated that some of these title compounds exhibited excellent insecticidal activities. The insecticidal activities of compounds 19a, 19b, 19d, 19g, 19k and 19m against oriental armyworm at 2.5 mg·kg-1 were 100%. The larvicidal activities of 19a, 19b, 19c, 19d, 19e, 19g and 19n against diamond-back moth were 100% at 0.1 mg·kg-1. Surprisingly, most of them still exhibited perfect insecticidal activity against diamond-back moth when the concentration was reduced to 0.05 mg·kg-1, which was higher than the commercialized Chlorantraniliprole.

Design, Syntheses and Biological Activities of Novel Anthranilic Diamide Insecticides Containing N-Pyridylpyrazole

In search of environmentally benign insecticides with high activity, low toxicity and low residue, a series of novel anthranilic diamide derivatives containing N-pyridylpyrazole was designed and synthesized. All the compounds were characterized by H NMR spectroscopy and elemental analysis. The single crystal structure of com pound 8j was determined by X-ray diffraction. The insecticidal activities of the new compounds were evaluated. The results show that some compounds exhibited moderate insecticidal activities against Lepidoptera pests. Among this series of compounds, compounds 80 and 8p showed 100% larvicidal activity against Mythimna separate Walker, Plutella xylostella Linnaeus and Laphygma exigua Hubner at a test concentration of 200 mg/kg, which is equal to the commercial chlorantraniliprole.

新型邻甲酰氨基苯甲酰胺类杀虫剂环溴虫酰胺及其开发应用

新型邻甲酰氨基苯甲酰胺类杀虫剂环溴虫酰胺具有与氯虫苯甲酰胺相似的化学结构和相同的杀虫机理。通过变构调节鱼尼丁受体,环溴虫酰胺对鳞翅目、双翅目和鞘翅目等多类害虫表现出了高杀虫活性,同时对哺乳动物、有益节肢动物和环境的影响较小。环溴虫酰胺的杀虫谱广、用量低、不感温、持效期长,可作为氯虫苯甲酰胺的重要补充。环溴虫酰胺可共用氯虫苯甲酰胺和溴氰虫酰胺的关键中间体进行生产,再制成单剂或复配,单用或与多种杀虫杀菌剂混合使用,一次施用即可同时控制水果、蔬菜、玉米、茶树和草坪等作物上的多种害虫。环溴虫酰胺的市场潜力较大,其开发应用情况值得关注。