Molecular modifications of benzylphenol and benzyl-1,3-benzodioxole types of insect chemosterilants

Rationally planned structural modifications were carried out on benzylphenols and benzyl-1,3-benzodioxoles described as fly chemosterilants and as anti-juvenile hormones. The introduction of a prop-2-ynyloxy group at various sites of the molecule resulted in compounds with a moderate inhibitory action on cytochrome P-450 mono-oxygenases, as measured by aldrin epoxidation. One compound, 5-(4-methoxybenzyl)-6-prop-2-ynyloxy-1,3-benzodioxole, revealed chemosterilant activity on Phormia regina, but its activity was less than that of the parent compounds. 2,4-Di-tert-butyl-6-[4-(3-methoxy-3-methylbutoxy)benzyl]phenol, which possessed a juvenoid structure, revealed no juvenile hormone (JH) activity but showed a high sterilant effect against Dysdercus cingulatus. In contrast to the parent substances, none of the tested compounds showed a detectable anti-JH effect in the Galleria assay. 8-Methoxy-2,3-methylenedioxydibenz[b,e]oxepine, a hitherto undescribed fused heterocyclic ring system, was devoid of activity, indicating the importance of free rotation and/or molecular flexibility. In spite of the moderate activities of these compounds, the manifold biological potential of the quinone-methide mechanism justifies further research on these lines.     

嘧啶联吡唑甲酰胺类化合物的合成及除草活性

设计合成了一系列结构新颖的嘧啶联吡唑甲酰胺类化合物5a~5o,其结构均经过1H NM R和MS分析确证。初步生物活性测试结果表明:在有效成分150 g/hm2剂量下苗后茎叶喷雾处理时,化合物(R)-N-[1-(4-氯苯基)乙基]-3-二氟甲基-1-(4,6-二甲氧基嘧啶-2-基)-1H-吡唑-4-甲酰胺(5c)、N-[1-(4-氯苯基)乙基]-1-(4,6-二甲氧基嘧啶-2-基)-N-甲基-3-三氟甲基-1H-吡唑-4-甲酰胺(5i)和N-[1-(4-氯苯基)乙基]-1-(4,6-二甲氧基嘧啶-2-基)-3-三氟甲基-1H-吡唑-4-甲酰胺(5k)对繁缕Stellaria media的抑制率高达90%以上;而同样剂量下苗前土壤喷雾处理时,化合物N-[1-(4-氯苯基)乙基]-3-二氟甲基-1-(4,6-二甲氧基嘧啶-2-基)-1H-吡唑-4-甲酰胺(5b)和5c对繁缕的抑制率达100%。该类结构化合物有望作为除草先导化合物进行开发。     

香豆素类化合物对朱砂叶螨的触杀活性及定量构效关系研究

采用玻片浸渍法,测定并筛选了25种具有代表性的香豆素类化合物对朱砂叶螨Tetranychus cinnabarinus雌成螨的触杀活性,并构建了一个预测能力较强的定量构效关系(QSAR)模型。结果表明:所有供试化合物对朱砂叶螨均具有触杀活性,且随着处理时间的延长活性升高。处理48 h后,LC50值低于1000 mg/L的化合物有8个,分别是3-(2-苯并咪唑)-7-(二乙氨基)香豆素(1)、3-(2-苯并噻唑)-7-(二乙氨基)香豆素(2)、3-氨基香豆素(3)、3-乙酰基香豆素(4)、4-甲氧基香豆素(5)、6-硝基香豆素(8)、6,7-二甲氧基香豆素(13)和7,8-二羟基香豆素(21),其中化合物1、2、3、5和13的杀螨活性优于药剂对照螺螨酯或与其活性相当;活性最好的化合物为13,处理48 h和72 h后LC50值分别为284.8和122.2 mg/L,其毒力约为螺螨酯的2倍。通过计算得到25种香豆素类化合物的34种物化参数,以此为描述子,经过SPSS相关性剔除、逐步回归分析和校正,得到一个以扭转力、取向力、总能量和分子半径为自变量的QSAR模型,该模型复相关系数R达到0.987,复判定系数R2也达到0.967,通过F检验证明上述模型具有较高的预测能力。     

新型含吡唑杂环邻氨基苯甲酰胺类化合物的合成与杀螨活性

以氯虫苯甲酰胺和氟虫腈的结构为基础,通过活性亚结构拼接的方法,设计合成了24个新型含吡唑杂环邻氨基苯甲酰胺类化合物,其结构经1H NM R、IR及APCI-M S表征。初步生物活性测试结果表明:化合物5-溴-N-[4-氯-2-甲基-6-(甲氨基甲酰基)苯基]-1-1-[2,6-二氯-4-(三氟甲基)苯基]-4-三氟甲基亚磺酰基-1H-吡唑-3-甲酰胺(5k)和5-溴-N-[4-溴-2-甲基-6-(甲氨基甲酰基)苯基]-1-[2,6-二氯-4-(三氟甲基)苯基]-4-三氟甲基亚磺酰基-1H-吡唑-3-甲酰胺(5l)在500 mg/L下对朱砂叶螨Tetranychus cinnabarinus的致死率为100%,但在100 mg/L下其致死率则分别降至30%和50%。所得结果可为邻氨基苯甲酰胺类化合物构效关系研究提供参考。     

Structural Effects of N-Arylcarbamoylpyrazolines on Calcium Uptake in Rat Brain Synaptosomes

N-Arylcarbamoylpyrazolines with various substituents at the para position of the carbamoyl benzene ring inhibited ATP-dependent Ca²⁺-uptake in synaptosomes prepared from the rat brain. The activity of these compounds was evaluated as log(1/I₅₀), the reciprocal logarithm of half inhibitory concentration, I₅₀ (m ), from the concentration–response curve for the inhibition of Ca²⁺-uptake. Among the compounds tested, methyl 3-(4-chlorophenyl)-4-methyl-1-[N-(4-trifluoromethylphenyl)carbamoyl]-2-pyrazoline-4-carboxylate was the most potent, the I₅₀ value of which as 9·12×10⁻⁷ m . Variations in the activity in terms of log(1/I₅₀) were quantitatively analysed using a substituent parameter, showing that the higher the electron-withdrawing effect of the substituent, the higher was the activity. The substituent effects were similar to those on insecticidal activity against the Americal cockroach. The higher the inhibitory activity against Ca²⁺ uptake, the higher seemed to be the insecticidal activity. Methyl(4S) - 3 - (4 - chlorophenyl) - 4 - methyl - 1 - [N - (4 - chlorophenyl)carbamoyl] - 2 - pyrazoline -4-carboxylate had higher inhibitory activity against Ca²⁺-uptake and higher in-secticidal activity than the R-isomer, but the difference was greater in theCa²⁺-uptake system.     

Inhibition of Echinochloa crus-galli var. frumentacea seedling root elongation by chiral 1, 3, 5-triazines in the dark

2-z-Substituted benzylamino-4-substituted-amino-6-chloro-1,3, 5-triazines are herbicidal compounds showing leaf-burning and/or growth inhibition with concomitant greening and stunting. Effects of chiral 1,3,5-triazine compounds in a light-independent seedling root elongation test with Echinochloa crus-galli var. frumentacea Wight demonstrated an interaction between chirality and root growth inhibition. The test compounds inhibited root growth, and this inhibition was due to interference with a system or systems other than photosynthesis. 4-(R)-sec-butylamino-2-(α,α-dimethylbenzyl)amino-6-chloro-1,3, 5-triazine showed the highest inhibitory activity, and 4-methylamino-2-(R)-a-methylbenzylamino-6-chloro-1,3,5-triazine was second. The chiral requirement for a strong inhibition of root growth was the (R)-configuration, contrasting with the requirement for the (S)-configuration for an inhibition of photosystem II.     

异香豆素噁二唑类化合物的合成及除草活性

为了寻找具有较高除草活性的异香豆素类化合物,设计合成了16个新型异香豆素噁二唑类化合物4a～4p,其结构均经核磁共振氢谱、碳谱及高分辨质谱确证。初步除草活性测定结果表明,部分目标化合物在500 mg/L下对马唐Digitaria sanguinalis L.和反枝苋Amaranthusretroflexus L.具有一定的除草活性,其中化合物4j（4-[5-（4-氯-苯基）-[1,2,4]二唑-3-基]-3-己基-6,7-二甲氧基异香豆素）的活性最好,对马唐和反枝苋的致死率分别为64%和62%。     

吡啶联三唑类衍生物的合成及杀虫活性

以3-氨基-2-氯吡啶(1)为起始原料,经重氮化、叠氮化、环合和酰氯化反应,生成1-(2-氯吡啶-3-基)-5-甲基-1H-1,2,3-三唑-4-甲酰氯(5),(5)与取代苯胺反应,制得13个未见文献报道的吡啶联三唑类化合物,其结构通过 1H NMR和LC-MS表征。初步生物活性测定结果表明:在500 mg/L质量浓度下,所有目标化合物对粘虫 Mythimna separate 均有一定的杀虫活性,部分化合物致死率达100%;但在100 mg/L下,除化合物ZJ-7的致死率仍达100%外,其余化合物的活性明显降低,甚至无活性。     

山蒟中脂肪链酰胺类化合物的分离及杀虫活性

采用提取、萃取及柱层析等方法,从山蒟Piper hancei Maxim甲醇提取物的石油醚和氯仿萃取相中分离到6个脂肪链酰胺类化合物,通过核磁共振、质谱并结合相关文献比对,其结构被分别鉴定为已知化合物chingchengenamide A( C1 )、N-异丁基-反-2-反-4-癸二烯酰胺( C2 )、假荜拨酰胺A( C3 )、荜茇宁( C4 )、N-p-香豆酰酪胺( C5 )和N-反式-阿魏酰酪胺( C6 ),其中 C1 为首次从山蒟中获得。利用幼虫浸液法测试了各化合物对白纹伊蚊Aedes albopictus和致倦库蚊Culex pipiens quinquefasciatus幼虫的12 h杀虫活性。结果表明:在20 mg/L下,化合物 C1 对白纹伊蚊的杀虫活性较高,其校正死亡率为100%,LC₅₀值为5.37 mg/L;化合物 C1 、 C2 、 C3 和 C4 对致倦库蚊的杀虫活性较高,20 mg/L下的校正死亡率分别为100%、88.5%、100%和100%,LC₅₀值分别为1.03、9.68、3.08和2.87 mg/L。     

Pyrazole phenyl ether herbicides inhibit protoporphyrinogen oxidase

Two isomeric pairs of pyrazole phenyl ether herbicides [AH 2.429, 4-chloro-1-methyl-5-(4-nitrophenoxy)-3-(trifluoromethyl)-1H-pyrazole; AH 2.430, 4-chloro-1-methyl-3-(4-nitrophenoxy)-5-(trifluoromethyl)-1H-pyrazole; AH 2.431, 5-((4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)oxy)-2-nitrobenzoic acid; and AH 2.432, 5-((4-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)oxy)-2-nitrobenzoic acid were evaluated for herbicidal activity in both intact plants and in tissue sections. Their capacity to induce accumulation of porphyrins in tissue sections and to inhibit protoporphyrinogen oxidase (Protox) in vitro were determined. In whole plant tests, the order of herbicidal activity was AH 2.430 AH 2.431 > AH 2.429 > AH 2.432. AH 2.430 consistently caused light-dependent membrane leakage in both green and far-red light grown cucumber cotyledon and barley primary leaf tissue sections after incubation for 20 hr in darkness in 0.1 mM solutions. The same treatment caused marked increases in protoporphyrin IX (PPIX) content during the 20-hr dark incubation. AH 2.429 and 2.431 were less effective and not effective in all tissues in causing herbicidal damage and PPIX accumulation. AH 2.432 was ineffective in tissue section assays. Mg-PPIX levels were not significantly affected by any of the compounds. Protochlorophyllide levels were decreased by AH 2.430 and 2.431 in barley and increased by AH 2.429, 2.431, and 2.432 in cucumber. A positive relationship was found between herbicidal activity and the amount of PPIX that was caused to accumulate by each compound. All of the compounds inhibited Protox activity. Positive correlations were found between herbicidal activity in planta over a 300-fold range and in vitro Protox inhibition and the amount of PPIX caused to accumulate in vivo. These data support the view that the pyrazole phenyl ethers exert their herbicidal activity entirely through inhibition of Protox.     

Synthesis and insecticidal activity of novel 1,3,4-oxadiazolin-5-one and pyrazolin-5-one derivatives

A series of novel 2-(2,4,6-trisubstituted phenyl)-1,3,4-oxadiazolin-5-one derivatives and 3-(2,4,6-trichlorophenyl)pyrazolin-5-one derivatives were synthesized and evaluated for insecticidal activity. It was found that a moderately bulky alkyl group, such as a tert-butyl group, on the heterocyclic ring, and a trifluoromethyl group on the benzene ring were optimal substituents on the molecule. The oxygen atom in the oxadiazoline ring was essential for insecticidal activity. Of the compounds assayed, 4-tert-butyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-5-one gave the highest activity against Nephtotettix cincticeps, with an LC₅₀ value of 0.51 mg litre⁻¹. © 1999 Society of Chemical Industry     

The pyrethrins and related compounds. Part XXXVII. synthesis and insecticidal properties of new 1-aryl-1-(3-arylpropyl and -propenyl)cyclopropanes (non-ester pyrethroids)

New routes to the title compounds, involving improved conditions for the cyclopropanation, and a new method of constructing the central three-carbon unit (based on the coupling of a Grignard reagent with an allylic acetate) give access to products for which the previously reported route was not satisfactory. For the new route, a synthesis of 5-bromo-2-fluoro-diphenyl ether was developed. Previously deduced relationships between structure and insecticidal activity apply for the new compounds: alkenes are generally more active than corresponding alkanes; substitution at the 3- or 4-position (but not the 2-) of the 1-aryl group can enhance activity. In addition, some fluorine-containing substituents lead to high activity.     

Pyridyl terpenoid ethers with high juvenile hormone activity

Pyridyl terpenoid ethers have outstanding juvenile hormone activity in Tenebrio molitor compared with their phenyl analogues (6,7-epoxy-3,7-dimethyloct-2-enyl 6-ethyl-3-pyridyl ether and 7-ethoxy-3,7-dimethyloct-2-enyl 6-ethyl-3-pyridyl ether are active at 100 pg/larva). The compounds were also active in Galteria mellonella and Culex pipiens.     

The role of glutathione S-transferases in the detoxification of some organophosphorus insecticides in larvae and pupae of the yellow mealworm,Tenebrio molitor (Coleoptera: Tenebrionidae)

The correlation between the natural levels of glutathione S-transferase (GST) and the tolerance to the organophosphorus insecticides parathion-methyl and paraoxon-methyl, as well as the interaction of affinity-purified enzyme and the insecticides were investigated in order to collect further information on the role of the glutathione S-transferase system as a mechanism of defence against insecticides in insects. The studies were carried out on the larvae and pupae of the coleopteran Tenebrio molitor L, which exhibit varying natural levels of GST activity. Stage-dependent susceptibility of the insect against insecticides was observed during the first 24 h. However, 48 h after treatment, the KD₅₀ value increased significantly due to the recovery of some individuals. Simultaneous injection of insecticide with compounds which inhibit GST activity in vitro caused an alteration in susceptibility of insects 24 or 48 h post-treatment, depending on stage and insecticide used. Inhibition studies combined with competitive fluorescence spectroscopy revealed that the insecticides probably bind to the active site of the enzyme, thus inhibiting its activity towards 1-chloro-2,4-dinitrobenzene in a competitive manner. High-performance liquid chromatography and gas chromatography revealed that T molitor GST catalyses the conjugation of the insecticides studied to a reduced form of glutathione (GSH). From the above experimental results, it is considered that GST offers a protection against the organophosphorus insecticides studied by active site binding and subsequent conjugation with GSH. © 2001 Society of Chemical Industry     

Control of Solenopsis invicta with delayed-action fluorinated toxicants

The fire ant, Solenopsis invicta Buren, was accidentally imported into the southern United States and has become a serious medical and agricultural pest of nine southeastern states and Puerto Rico. For a bait toxicant to be effective in fire ant control it must have delayed activity over a wide range of concentrations. Less than 1% of the 7500 compounds screened since 1958 has had delayed action. This paper describes several classes of fluorinated compounds that exhibit delayed activity. These compounds are used to illustrate the following three approaches to the discovery of delayed-action toxicants: (a) random screening of compounds for delayed action; (b) design of delayed activity through the synthesis of pro-insecticides; and (c) serendipity. As a result of these investigations two new classes of insecticides were discovered. A compound from one of these classes (tetrahydro-5,5-dimethyl-2(1H)-pyrimidinone (3-(4-(trifluoromethyl)phenyl)-1-(2-(4-(trifluoromethyl)phenyl)-ethynyl)-2-propenyl-idene) hydrazone, has been commercialised, while one or more compounds from the second new chemical class (fluorinated sulphonamides) are under development. Fluorinated delayed-action insecticides have made significant contributions to current fire ant control and will no doubt play a role in the future.     

Synthesis and structure–activity relationships for anticipated molluscicidal activity of some 2-amino-5-substituted pyridine derivatives

A series of 2-amino-5-substituted pyridine derivatives was synthesized and their molluscicidal activity against white garden, Theba pisana (Müller), and brown garden, Helix aspersa (Müller), snails was investigated by two methods of application. Some of these compounds showed strong activity under laboratory conditions against the two types of snail. T pisana was more sensitive to the tested compounds than H aspersa. The most effective compounds were 2-amino-5-(benzotriazole-1-ylmethyl)-3-methylpyridine, 2-amino-5-[1-(benzotriazole-1-yl)nonyl]-3-methylpyridine and 2-[(1,2,4-triazole-1-ylmethyl)amino]-3-methylpyridine which exhibited high molluscicidal activity. The toxicity results are discussed in relation to the chemical structures. © 1999 Society of Chemical Industry     

Acaricidal properties of some synthetic unconjugated allenic anilides

Seven unconjugated allenic anilides with the allenic moiety situated at the 3, 4 position were synthesized and evaluated for acaricidal activity against Boophilus microplus (Canestrinii). The order of toxicity (% adult mortality) of the anilides against adult B. microplus at 0.5 μg tick^?1 was: N-(3-chloro-4-methyl-phenyl)-5-methylhexa-3, 4-dienamide, (I) = N-(4-bromophenyl)-5-methylhexa-3, 4-dienamide(III)(100%) > N-(4-bromophenyl)-deca-3, 4-dienamide (VI)(68%) > N-(3, 4-dichlorophenyl)-5-methylhexa-3, 4-dienamide (II) (32.3%) > N-(3, 4-dichlorophenyl)-5-methylhepta-3, 4-dienamide (IV) (28%) > N-(3-chloro-4-methylphenyl)-5-ethylhepta-3, 4-dienamide (VII) (24%) > N-(4-bromophenyl)-5-methylhepta-3, 4-dienamide (V) (20%). Comparison of the relative potencies (in parenthesis) at 1.5 μg tick^?1 of the anilides with three commercial acaricides: pyrenone, lindane and carbaryl, revealed the following orders of activities: in comparison with pyrenone: pyrenone = I = II (1) > VI(0.93) > II (0.67) > IV (0.55) > VII (0.46) > VI (0.37); in comparison with lindane: I = HI (6.06) > VI (5.65) > II (4.04) > IV (3.36) > VII (2.76) > V (2.39) > lindane (1.0). All anilides were more toxic than carbaryl which gave no mortality at 1.5 μg tick^?1. The need for developing more effective control agents for B. microplus is highlighted by the high levels of resistance found in some Jamaican populations of the pest. Resistance of the orders of 31- to 227-fold had been reported against lindane and between 15- and 67-fold to carbaryl.     

New chlorinated juvenile hormone analogues and their biological activity

In the search for new juvenile hormone analogues (JHAs), a general approach was chosen based on the substitution of the isoprene unit, that carries the epoxy function in the natural hormone JHIII, by 3,3,3-trichloropropyl, 2,2-dichlorocyclopropyl- methyl, 3,3-dichloroallyl, or 3-chloroprop-2-ynyl groups. Accordingly, several terpenoid aromatic JHAs were prepared with, or without, oxygen atoms in the aliphatic chain. Structure-biological activity relationships of the most active compounds toward the yellow mealworm (Tenebrio molitor) and the large cabbage white butterfly (Pieris brassicae) are given. With a view to preparing synthetically accessible analogues, some alkyl phenyl ethers were also made, which were not branched in the aliphatic chain and were related terminally to the most active compounds. They were only moderately active against insects when tested for morphogenetic activity, but exhibited a good field persistence. The occurrence of a moderate acaricidal activity among these analogues prompted the examination of several 1,4-disubstituted-phenyl derivatives. The ovicidal effectiveness of these products against a susceptible strain of the two-spotted spider mite, Tetranychus urticae, was ten or 100 times higher than that of the well known and highly potent JHAs.     

Novel acetylcholinesterase inhibitors: Synthesis and structure–activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives

Based on the multiple binding sites of acetylcholinesterase (AChE), a series of AChE inhibitors: phthalimide alkyloxyphenyl N,N-dimethylcarbamate were designed and synthesized. AChE inhibitory activity and structure–activity relationship of the compounds were researched also. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different alkyloxy chain length and position between phthalimide and phenyl N,N-dimethylcarbamate (PDM). The biological properties of the series were investigated by considering the activity on isolated enzyme. Some of the newly synthesized derivatives, when tested on isolated AChE from head of housefly (Musca domestica), were more active than PDM. The compounds J1, J2 and K1–K8 demonstrated higher inhibitory activity (5- to 404-fold) for AChE than that of PDM. In particular, compound K1 displayed the best AChE inhibition (404-fold higher than PDM), which suggested that phthalimide group of K1 strongly bound at the residues lining the gorge while phenyl N,N-dimethylcarbamate bound at the catalytic site.     

Synthesis and Structure–Activity Relationships of Miticidal 4,5-Dihydropyrazole-5-thiones

A series of novel 4,5-dihydropyrazole-5-thiones (DHPs) was synthesised by treating the corresponding dihydropyrazolones with ‘Lawesson’s reagent and evaluated for miticidal activity against two-spotted spider mites (Tetranychus urticae Koch). Of these, 3-(4-chlorophenyl)-4,4-dimethyl-1-phenyl-4,5-dihydropyrazole-5-thione, 3-(4-chlorophenyl)-4-ethyl-4-methyl-1-phenyl-4,5-dihydropyrazole-5-thione, 3-(4-chlorophenyl)-1-phenyl-4,5-dihydropyrazole-5-thione-4-spirocyclopentane and 4,4-dimethyl-1-phenyl-3-(4-trifluoromethyl-phenyl)-4,5-dihydropyrazole-5-thione were highly active (pEC₅₀>4·0) and were more effective than the miticide dicofol (pEC₅₀=3·879), which has traditionally been used for the control of phytophagous mites. Structure–activity relationship (SAR) studies were performed on each position of the pyrazole ring of DHPs. The results indicated that the unsubstituted phenyl, 4-substituted phenyl and thioxo groups on the 1-, 3- and 5-positions of DHPs respectively were required for activity. Quantitative SAR studies using physicochemical parameters of substituents and the capacity factor k′ as a hydrophobicity index suggested that: (a) the activities of all types of DHPs examined were mainly dominated by hydrophobicity, (b) the bulkiness of 4-substituents of the 3-phenyl ring favoured the activity and (c) the log k′ optimum for all DHPs was 1·675, equivalent to a log P_ow value of c. 5·0.