Cytochrome P-450 Inducers and Inhibitors Interfering with Ecdysone 20-Monooxygenases and Their Activities during Postembryonic Development of Neobellieria bullata Parker

The cytochrome P-450-dependent microsomal and mitochondrial ecdysone 20-monooxygenase systems convert ecdysone into 20-hydroxyecdysone. The microsomal fraction of fat bodies of zero h wandering stage fleshfly larvae (Neobellieria bullata; Diptera: Sarcophagidae) has a high ecdysone 20- monooxygenase activity. The effects of cytochrome P-450 inhibitors were investigated in vitro on microsomal ecdysone 20-monooxygenase. Metyrapone, fenarimol and certain imidazole derivatives (KK-42, KK-110, KK-135 and PIM) are strong inhibitors. The IC₅₀ value of KK-110, which is the strongest inhibitor, is 2 × 10^?7 M. A triazolyl and two cyclopropylamine derivatives have low activity. The activities of different NADPH-cytochrome c (P-450) reductase inhibitors were also assessed; diquat dibromide is a moderate inhibitor of microsomal ecdysone 20-monooxygenase, while paraquat dichloride has no activity. In-vivo experiments with cytochrome P-450 inducers and inhibitors gave the following results: (a) fenarimol, FI-121, precocene-2 caused “permanent” first-instar larvae; (b) barbital, phenobarbital and their sodium salts caused significant delay in larval development; (c) PIM, PTM, metyrapone, KK-42, KK-135, J-2710, RH 5849 and colchicine caused moulting disturbances; (d) J-2710, PIM, PTM, KK-42, KK-135, RH 5849 and colchicine caused lethal spiracle and mandible malformation; (e) KK-110, fenarimol, barbital and phenobarbital caused precocious pupariation.     

Effects of anti-ecdysteroid azole analogues of metyrapone on the larval development of the fleshfly,Neobellieria bullata

Based on our previous finding that PIM (phenyl-imidazolyl-metyra-pon; 2-(1-imidazolyl)-2-methyl-1-phenylpropan-1-one, 1) is a strong inhibitor of ecdysone 20-monooxygenase (IC₅₀ = 7.89 × 10^?7 M) from the fleshfly, Neobellieria bullata (Parker) and has also a good toxic action in vivo against this insect, 17 imidazole and 1,2,4-triazole analogues of metyrapone were synthesized and evaluated for their action against N. bullata larvae in terms of toxicity, length of larval development, weight of the puparium as well as special symptoms, i.e. malformations of the anterior and posterior spiracles, and of the mandibles. The introduction of p-methoxy (LC₅₀ = 49 mg kg^?1 in diet) or p-chloro (LC₅₀ = 97 mg kg^?1) substituents on the benzene ring of PIM resulted in a significant increase in toxicity compared to that of metyrapone (LC₅₀ = 561 mg kg^?1) and PIM (LC₅₀ = 148 mg kg^?1). The hybridization state of the carbon atom adjacent to the benzene ring was not an important factor for toxicity because the acetoxy derivative ( 13 ) was almost as toxic as PIM. At least one methyl group was required on the carbon atom adjacent to the azole ring to maintain activity, while an ethyl group ( 4 ) enhanced the toxic effect. At the applied doses some compounds including metyrapone itself, extended the duration of the larval development. Only metyrapone and PIM decreased the puparium weight. Several derivatives induced lethal malformations of mandibles as well as the anterior and posterior spiracles.     

7Th international congress of pesticide chemistry

A series of 2-(1,3-dimethyl-4-substituted-5-pyrazolyl)sulfonylimino-5,7-disubstituted-2H-1,2,4-thiadiazolo[2,3-a]pyrimidines was synthesized and tested for herbicidal effects. The compounds showed potent activity and improved selectivity to rice when compared with analogous sulfonylurea derivatives.     

Phototransformation of Triadimefon on Glass and Soil Surfaces

Photodegradation of triadimefon has been studied on glass and soil surfaces. A number of photoproducts have been isolated and characterised by NMR, IR and MS. Photolysis resulted in considerable amounts of 1-(4-chlorophenoxymethyl)-1,2,4-triazole, 1-(4-chlorophenoxy)-2,2-dimethyl-1-(1,2,4-triazol-1-yl)propane, 1-(1,2,4-triazol-1-yl)-3,3-dimethylbutan-2-one and 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-ol. Rates of photodegradation on glass and soil surfaces under UV and sunlight followed first-order kinetics with a significant correlation coefficient. Photodegradation was greater on alluvial soil than on laterite soil.     

Structural studies in azolylmethanes

The crystal structures of a number of fungicidal azolylmethanes are compared. In the benzyl compounds [1-aryl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)pentan-3-ones, the corresponding pentan-3-ols, and 1-(4-chlorophenyl)-3-(2-fluorophenyl)-2-(1,2,4-triazol-1-yl)propan-1-one], the benzyl and tert-butyl groups (or 4-chlorophenyl group) are trans, whereas in the analogous phenoxy compounds [1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one and the corresponding butan-2-ol], the tert-butyl groups are trans to the triazole and gauche to the phenoxy group. Coupling constants, determined by nuclear magnetic resonance (n.m.r.) spectroscopy, suggest that for some compounds there is one dominant solution conformation. Intramolecular hydrogen bonding, observed by infrared spectroscopy in two of the compounds, supports the findings by n.m.r. For some compounds, the crystal and solution conformations appear to be very similar, whereas in others they are quite different. Published data on the relative activity of the enantiomers of the benzyl- and phenoxy-compounds are discussed, but differences in the relative activity of enantiomers in the two series cannot be readily rationalised. It is concluded that different enantiomers may have different modes of binding at the active site.     

Inhibition of insect cytochrome P-450 by some metyrapone analogues and compounds containing a cyclopropylamine moiety and their evaluation as inhibitors of juvenile hormone biosynthesis

Two metyrapone analogues, 2-(l-imidazolyl)-2-methyl-l-phenyl-l-pro-panone (A-phenyl-B-imidazolyl-metyrapone; III) and 2-methyl-l-phenyl-2-{1,2,4-triazol-l-yl)-l -propanone (A-phenyl-B-triazolyl-meiyrapone; IV) as well as two cyclopropylamine derivatives. N-cyclopropyl-4-icrt-butylbenzylamine (V) and N-cyclopropyl-4-(3,7-dimethyl-7-methoxy-octyloxy)benzamide (cyclopropylamine acylated with a JH analogue acid of known structure; VI) were synthesized and evaluated in biological assays for JH biosynthesis on cockroach, Diploptera punctata corpora allata and egg growth in adult cockroach as well as for mixed function oxidase activities, i.e. epoxidation of aldrin to dieldrin and O-demethylation of 7-methoxy-4-methylcoumarin to 7-hydroxy-4-methylcoumarin on microsomes from housefly, Musca domestica, abdomen and from cockroach midgut. Compound VI was a good in-vitro inhibitor of JH biosynthesis, but it had significantly lower activities in the assays for inhibition of microsomal cytochrome P-450. Compound IV and metyrapone had moderate activity as inhibitors of oocyte growth. Compounds III, IV and V were more potent inhibitors of housefly aldrin epoxidation than metyrapone and they inhibited the enzyme activity by almost 100% at 02mM, while in cockroach midgut microsome assay metyrapone was more potent than these three compounds.     

2-(5,7-二甲基-1,2,4-三唑[1,5-a]嘧啶-2-硫代)乙酰胺类化合物的合成及除草活性

以芳胺或取代稠杂环胺、氯乙酰氯和2-巯基-5,7-二甲基-1,2,4-三唑 嘧啶为原料,合成了8个含稠杂环及芳环的三唑并嘧啶类新化合物,结构经1H NMR, MS 和IR确证,初步测定了该类化合物在室温下对稗草等3种禾本科杂草和反枝苋等3种阔叶杂草芽前芽后的抑制率,结果表明:有6个化合物在有效剂量75 g/hm2下的抑制率超过80%。     

Binding of azole fungicides related to diclobutrazol to cytochrome P-450

Fungicides containing the imidazole and triazole groups are known to block the 14α-demethylation reaction in ergosterol biosynthesis, which is a cytochrome P-450 enzyme system. Fungicides related to diclobutrazol [(2RS, 3RS)-1-(2,4-dichlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)pentan-3-ol] bind to cytochrome P-450 in rat liver microsomes, whole yeast cells, yeast microsomes and to a partially purified cytochrome P-450 from yeast, with Type II spectral changes. The most fungicidally active isomer (2R, 3R) shows greater binding than the less active (2S, 3S)-enantiomer to yeast microsomes; when the cytochrome P-450 was purified, a preparation was obtained to which binding more closely matched the fungicidal activity. Binding to rat liver microsomes does not reflect the fungicidal activity of the compounds.     

Synthesis and fungicidal activity against Pyricularia oryzae of 6-(1,2,4-triazol-4-yl) chromone and -1-thiochromone derivatives

A series of novel 6-(1,2,4-triazol-4-yl) chromone and -1-thiochromone (benzo[b]thiazin-4-one) derivatives was obtained by cyclisation via thiosemicarbazides which were prepared by reaction of hydrazines and the corresponding isothiocyanates. Their fungicidal activity was evaluated against the rice blast fungus Pyricularia oryzae. Of this series, 2,5,8-trimethyl-6-(1-propyl-5-thioxo-3-trifluoromethyl-1,2,4-triazol-4-yl) chromone, 6-(1-butyl-5-thioxo-3-trifluoromethyl-1,2,4-triazol-4-yl)-2,5,8-trimethylchromone, 6-(1-hexyl-3-methyl-5-thioxo-1,2,4-triazol-4-yl)-2,5,8-trimethylchromone and 6-(1-allyl-5-thioxo-3-trifluoromethyl-1,2,4-triazol-4-yl)-2,5,8-trimethylchromone were highly active (pEC₅₀>6·0). Structure–activity relationship studies using the capacity factor k′ as a hydrophobicity index suggested that the log k′ optimum for 2,5,8-trimethyl-chromone and -1-thiochromone derivatives was around 1·0, equivalent to a log P_ow value of c. 4·4. © 1998 SCI     

The effect of C-2-carboxyphenyl derivatives of certain heterocyclic compounds on root geotropism in cress seedlings

The effects on root geotropism of 2-carboxyphenyl derivatives of various five- and six-membered heterocyclic compounds have been assessed. In an assay involving cress seedlings, appropriately substituted derivatives of isoxazole, 1,3,4- and 1,2,4- oxadiazoles, 1,3,4-thiadiazole, 1,2,4-triazole, thiazoie, pyridine, pyrimidine and pyridazine were highly effective in eliminating the geotropic response.     

N-取代苯基-1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙基氨基甲酸酯的合成及生物活性

为了寻找高活性的三唑类苯基氨基甲酸酯衍生物,以 1,2,4-三氮唑、2-氯-2,4-二氟苯乙酮为原料,采用活性亚结构拼接的策略,设计并合成了18个未见文献报道的N-取代苯基-1-(2,4-二氟苯基)-2-(1H-1,2,4-三唑-1-基)乙基氨基甲酸酯衍生物 6a ~ 6r 。其结构均通过 1H NMR、13C NMR和高分辨质谱（HRMS）的确证。抑菌活性测定结果显示:在100 μmol/L下,化合物 6m 对6种供试真菌具有良好的抑制作用,抑制率均达到50%以上。化合物 6p 对油菜菌核病菌Sclerotinia sclerotiorum的EC₅₀值为7.1 μmol/L,抑菌活性高于对照药剂烯唑醇（EC₅₀值9.1 μmol/L）。杀螨活性测定结果显示,在150 μmol/L时,化合物 6h 、 6k 和 6o 在48 h时对朱砂叶螨Tetranychus cinnabarinus的致死率分别为67.7%、74.9%和57.5%,杀螨活性低于对照药剂阿维菌素B1a(致死率100%)。本研究所合成的化合物 6o 兼具一定杀菌和杀螨活性,可为新型三唑类杀菌杀螨化合物的设计与研究提供参考。     

Photolysis of Diniconazole-M under Sunlight

The photodegradation of diniconazole-M [(E)-(R)-1-(2,4-dichlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-pentene-3-ol] was studied as thin film on glass surface under sunlight. Photoproducts were separated and identified by NMR, IR, UV and mass spectroscopy. They were characterised as the (Z)-isomer of diniconazole-M, a cyclic alcohol and its corresponding ketone and an isoquinoline derivative. © 1997 SCI.     

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     

Photolysis,metabolism and other factors influencing the performance of triadimefon as a powdery mildew fungicide

Triadimefon, 1-(4-chlorophenoxy)-3,3-dimethyl-1-( 1,2,4-triazol-1-yl)butanone, applied at low dosage rates to leaves of marrow, apple or barley plants gave effective control of the appropriate powdery mildew fungi. The compound appeared to be systemic and to have considerable vapour-phase activity. In marrow plants, up to 56% of triadimefon was metabolised to a mixture of two corresponding diastereoisomeric secondary alcohols. The mixture was identical with that obtained by chemical reduction of triadimefon. This mixture was also a very effective systemic fungicide and active in the vapour-phase. Triadimefon was also reduced when incubated with Aspergillus niger but this was important only in shake culture. In replacement culture experiments, mycelial mats of this fungus converted the compound into a different metabolite, its isopropyl analogue. This may have resulted from participation of triadimefon in the C-4 demethylation processes involved in fungal biosynthesis of ergosterol. Photolysis caused cleavage of the C-1 to triazole bond liberating 1,2,4-triazole, 4-chlorophenol and 4-chlorophenyl methyl carbonate, all of which were non-fungitoxic. The importance of this photolysis in the in-vivo situation is discussed.     

Diapause disruption with tebufenozide for early-instar control of the spruce budworm, Choristoneura fumiferana

In North America, the eastern spruce budworm, Choristoneura fumiferana Clem., is an important coniferous pest against which tebufenozide has proven effective as a control product. By acting as an ecdysone agonist, tebufenozide can induce precocious moulting in late (fifth-sixth) instars but can also be carried over to the next generation owing to its persistence on foliage. The authors conducted laboratory experiments on first-instar larvae treated with tebufenozide dissolved in acetone. Larvae exposed to doses equal to or above 0.1 microg cm(-2) displayed precocious moulting in the second instar after hibernaculum spinning, which effectively disrupted diapause. Larger doses induced moulting in first instars. Evidence is provided that this dose-response difference is related to whether or not an effective dose of tebufenozide is ingested by the first instar prior to the peak of moulting hormone (20-hydroxyecdysone) in first instars. Doses ineffective to kill first instars are carried over to the second instar, where they induce a precocious moult. This type of response to tebufenozide is dependent on the presence of a moulting machinery (the EcR-USP receptor complex) that is ready for ecdysone transduction. Interestingly, ecdysone levels are low in second instars, as measured by a radioimmunoassay, which suggests that diapause in spruce budworm is maintained by a suppression of ecdysone production. Thus, diapause disruption by tebufenozide may well provide an alternative control strategy for this important pest.     

Effects of the pyrethroids bioallethrin,deltamethrin and RU-15525 on the electrical activity of a cuticular mechanoreceptor of the cockroach Periplaneta americana

A study has been made of the effects of bioallethrin, RU-15525 [5-benzyl-3-furylmethyl (1R)-cis-2,2-dimethyl-3-(tetrahydro-2-oxo-3-thienylidenemethyl)-cyclopropanecarboxylate, ‘Kadethrin’], and deltamethrin on the electrical activity, measured in vivo, of a cuticular mechanoreceptor of Periplaneta americana. The modifications induced by these pyrethroids on the membrane excitability can be classified into two groups: Type I effects (bioallethrin) are characterised by a substantial increase in the number of action potentials triggered at the initiation site by a given mechanical stimulation, by an electrical activity persisting after mechanical stimulus has been stopped (repetitive activity), and possibly, by an inhibition of excitability of the cell membrane. Type II effects (RU-15525 and deltamethrin), are characterised by an inhibition of the excitability of the initiation site. In the case of RU-15525, there was a transient spontaneous electrical activity. Both types of effects have been linked to an action on the sodium channel, particularly at the initiation site. The preparation studied, which possessed no synapses, was shown to be more sensitive to deltamethrin (which is also the most insecticidal of the three pyrethroids) than to either allethrin or RU-15525. These results suggest that it is unnecessary to envisage a main target (sodium channel) that is different for the two types of pyrethroid.     

Inhibition of the fucosterol-24(28)-epoxide cleavage enzyme of sitosterol dealkylation in Spodoptera littoralis larvae

The conversion of sitosterol into cholesterol and the effect of inhibitors on the dealkylation reaction has been studied in Spodoptera littoralis Boisd. Using a microsomal preparation from the midgut of the larvae [³H]fucosterol and [³H]fucosterol-24,28-epoxide were converted into desmosterol and cholesterol in vitro, and a series of inhibitors were tested using the latter substrate. Triadimefon [1-(4-chlorophenox)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one] strongly inhibited the cleavage enzyme at 2 μM. In a functional group study we observed that (i) the phenoxy substituent was more strongly inhibitory than the corresponding benzyl, and (ii) when the ketone is reduced to the secondary alcohol in either phenoxy or benzyl series, inhibition decreased markedly. In the benzyl series of compounds we found that (iii) a 2,4- or 2,6-dichlorophenyl gave greater inhibition than mono-, tri-, or pentachlorophenyl derivatives, and (iv) changing the heterocyclic ring gave activity in the order 2-pyridyl=3-pyridyl=imidazole>pyrazole>triazole. In the triazole series, substitution of the hetero ring did not abolish inhibition. When either triadimefon or 22,25-diazacholesterol was incorporated into a diet (1000 ppm) containing sitosterol plus campesterol as the only sterol supplements and fed to final larval instar insects, the weight of the insects throughout the instar was reduced and the duration of the instar increased. Insects reared from the early third-instar stage on such a diet containing amounts of triadimefon had reduced percentages of cholesterol and desmosterol in the final larval instar with a proportional increase in the sitosterol level. Thus, inhibition of side chain cleavage has been obtained in vitro and in vivo, but the high concentrations of inhibitor required preclude the enzyme as a target for a novel class of insecticide.     

3-苄基-5-(1-(2-氧代-1-氧杂螺[4,5]癸-3-烯-3-基) 亚乙基)-2-氨基咪唑啉-4-酮类化合物的合成及杀菌活性

为寻找高活性的杀菌化合物,在前期合成5-(1-(4-甲基-2-氧代-1-氧杂螺[4,5]癸-3-烯-3-基) 亚乙基)-2-氨基咪唑啉-4-酮类化合物的基础上进行结构修饰,在咪唑啉-4-酮的3-位引入苄基,设计并合成了一系列未见文献报道的化合物,其结构经过核磁共振氢谱 (1H NMR)、碳谱 (13C NMR) 及高分辨质谱 (HR-ESI-MS) 确证。经高效液相色谱 (HPLC) 分析显示,Z-构型中间体化合物 6 在酸性条件下会发生氮质子化开环再环化,转化为E-构型化合物 7 。离体杀菌活性测定结果表明,3-位苄基的引入改善了该类化合物的杀菌活性,其中化合物 (E)-3-苄基-5-(1-(4-甲基-2-氧代-1-氧杂螺[4,5]癸-3-烯-3-基) 亚乙基)-2-(4-甲氧基苯基) 氨基-咪唑啉-4-酮 ( 9c ) 和 (E)-3-苄基-5-(1-(4-甲基-2-氧代-1-氧杂螺[4,5]癸-3-烯-3-基) 亚乙基)-2-(4-氟苯基) 氨基-咪唑啉-4-酮 ( 9h ) 对油菜菌核病菌的EC₅₀ 值分别为14.3和21.1 mg/L。活体杀菌活性测试结果显示,在400 mg/L下化合物 9c 对于黄瓜霜霉病和小麦白粉病的防治效果分别为 80%和85%。     

Synthesis and insecticidal evaluation of novel N-(S-amino)sulfenylated derivatives of diacylhydrazines

A series of new N-(S-amino)sulfenylated derivatives of diacylhydrazines were synthesized by the reaction of S-aminosulfenyl chlorides with N-tert-butyl-N'-benzoyl-N-substituted benzoylhydrazines in the presence of sodium hydride, and evaluated for moulting hormone mimicking activity. In the course of syntheses, N-N bond cleavage in diacylhydrazines was found and the reaction was studied in some detail. The results of bioassay showed that the title compounds exhibit excellent larvicidal activity. Toxicity assays indicated that these compounds can induce a premature, abnormal and lethal larval mount.     

Pyrimidinyl-substituted amides and thioureas: syntheses, crystal structure and herbicidal activities

BACKGROUND: The high herbicidal activities of [1,2,4]triazolo[1,5-c]pyrimidine and 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine derivatives suggested the development of new fused heterocyclic compounds for application as herbicides. RESULTS: Three series of pyrimidinyl-substituted thioureas (4) and amides (5, 6) were synthesized, and the typical crystal structure of a 2H-1,2,4-thiadiazolo[2,3-a]pyrimidine derivative (5a) was determined by X-ray diffraction. All the compounds were tested for herbicidal activity against selected weeds. CONCLUSION: The series of fused heterocyclic amides 5a to 5d exhibited high herbicidal activities both against monocotyledonous weeds (Echinochloa crus-galli L., Sorghum bicolor (L.) M?nch., Digitaria sanguinalis (L.) Scop) and against dicotyledonous weeds (Amaranthus retroflexus L. and Brassica campestris L.) in pre-emergence treatments. In particular, compound 5b at low concentration still showed high inhibitory activity against A. retroflexus in pre-emergence treatment. Different substituents at the meta positions of the pyrimidine ring were found to affect the herbicidal activity.