Journal of Pesticide Science

Normal insect development requires a precisely timed, precipitous drop in hemolymph juvenile hormone (JH) titer. This drop occurs through a coordinated halt in JH biosynthesis and increase in JH metabolism. In many species, JH esterase (JHE) is critical for metabolism of the resonance-stabilized methyl ester of JH. JHE metabolizes JH with a high k cat/K M ratio that results primarily from an exceptionally low K M. Here we review the biochemistry and structure of authentic and recombinant JHEs from six insect orders, and present updated diagnostic criteria that help to distinguish JHEs from other carboxylesterases. The use of a JHE-encoding gene to improve the insecticidal efficacy of biopesticides is also discussed.

IntroductionDiscoveryEfficacy Intrinsic Insecticidal ActivityActivity in Devices Heated FormulationsNon-heated FormulationsConclusion AcknowledgmentReferences Intrinsic Insecticidal ActivityActivity in Devices Heated FormulationsNon-heated Formulations Heated FormulationsNon-heated Formulations

IntroductionInteractions with Basic Residues Induce a Positive Charge in Neonicotinoids which Mimics the Quaternary Ammonium of AcetylcholineExploring Structural Features of nAChRs Contributing to the Selectivity of Neonicotinoids Employing the α7 nAChRHomology Modeling of nAChRs has Assisted in the Identification of Key Amino Acid Residues Involved in the Selective Interactions with Neonicotinoids of Heteromeric Nicotinic Acetylcholine ReceptorsConclusion AcknowledgmentsReferences

This study relates to the modification of 2-benzylamino-4-methyl-6-trifluoromethyl-1,3,5-triazine. New 1,3,5-triazine compounds with an electron-withdrawing carboxyl group, e.g. ester group, substituted for the trifluoromethyl group, were synthesized and assayed for activity to inhibit photosynthetic electron transport (PET) in thylakoids of spinach as well as both atrazine-resistant and wild-type Chenopodium album. Among the compounds with an alkylamino group, 2-ethoxycarbonyl-4-isopropylamino-6-methyl-1,3,5-triazine was the most potent PET-inhibitor, exhibiting a pI50 of 6.11. The inhibitory activity was generally more potent with 2-alkoxycarbonyl-4-(branched alkyl)amino-6-methyl-1,3,5-triazines than amino-analogues with straight chain alkyl groups or unsaturated alkyl groups. © Presticide Science Society of Japan

Carboxylesterases (CES, EC 3.1.1.1) are members of a superfamily of serine hydrolases that hydrolyze ester, amide, and carbamate bonds. Several different CES genes exist in mammalian species with evidence of multiple gene duplication events occurring throughout evolutionary history. There are five CES genes reported in the Human Genome Organization database, although CES1 and CES2 are the two best characterized human genes. An emerging picture of the CES family suggests that these enzymes have dual roles in the metabolism of xenobiotic and endobiotic compounds. Pesticides, such as the pyrethroids, are important xenobiotic substrates that are metabolized by CES, whereas cholesteryl esters, triacylglycerols, and 2-arachidonoylglycerol are examples of endobiotics known to be substrates for CES. Functional studies using selective chemical inhibitors, siRNA, and gene knockout models are providing valuable insights into the physiological functions of CES, and suggest that CES may be a novel target for the treatment of diseases such as diabetes and atherosclerosis. This review will examine the known physiological functions of CES, the interactions between xenobiotics (primarily pesticides) and lipids that occur with CES enzymes, and where possible the implications that these findings may have in terms of health and disease.

The pharmacophore of the neonicotinoid insecticide thiacloprid, cyanoiminothiazolidine, was modified to heterocycles such as imidazolidine, pyrrolidine and oxazolidine (the central ring hereafter). Their 6-chloro-3-pyridylmethyl or 5-chloro-3-thiazolylmethyl derivatives were examined for insecticidal activity against the American cockroach by injection and neuroblocking activity using the cockroach ganglion. The derivatives showed strong insecticidal activity with the minimum lethal dose (MLD) of about 10 nmol, which were however mostly weaker than the corresponding nitromethylene or nitroimine compounds. The activity was enhanced in the presence of synergists. The neuroblocking effect of cyanoimino compounds was at the micromolar level. Quantitative analysis for 23 variants of the key pharmacophore, constructed with the central ring conjugated to an NCN, CHNO2, or NNO2, showed that the neuroblocking potency is proportional to the Mulliken charge on the nitro oxygen atom or cyano nitrogen atom. The optimum log P value was evaluated as 1.19. The equation for the insecticidal- vs. the neuroblocking-potencies indicated that both potencies are related proportionally with each other when the other factors are the same.

Exposure of ¹⁴C-NK-049 labeled at the carbonyl carbon to UV light in water solution resulted in rapid decomposition. NK-049 was decomposed predominantly by ways of cleavage at the carbonyl group to produce m-toluic acid and 4-methoxy-3-methylbenzoic acid followed by the liberation of ¹⁴C-carbon dioxide. Other photodecomposition reactions observed were stepwise oxidation of 3 or 3’-CH3group, reduction of the carbonyl group and desmethylation of 4-OCH3group. When exposed to sunlight, NK-049 was rapidly decomposed both on glass and silica gel plates and in water in the same ways as that when exposed to UV light. More than 16 photodecomposed products from NK-049 were detected on tic and 10 of them were identified. Practically, no difference was observed between the photodecomposed products obtained by sunlight and those by UV light. NK-049 acts as an effective photosensitizer similar to benzophenone. Dieldrin was rapidly photoconverted to intramolecular bridged photodieldrin by sunlight exposure in the presence of NK-049. © 1979, Pesticide Science Society of Japan. All rights reserved.

The fate of 3,3′-dimethyl-4-methoxybenzophenone (methoxyphenone, NK-049) in paddy soils and its metabolism by soil microorganisms were investigated by using ¹⁴C-NK-049 labeled at carbonyl carbon. NK-049 disappeared rapidly under static (“anaerobic”) flooded conditions with half-life of about 10 days. Main products obtained were 3,3′-dimethyl-4-hydroxybenzophenone (NK-049-OH) and ¹⁴CO2. Oxidized products of 3- or 3′-methyl group and reduced form at carbonyl group of NK-049 were also detected by thin layer chromatography (tlc). After 2 weeks of incubation, radioactivity of NK-049-OH reached 43.0 and 70.8% of the applied radioactivity in Mito soil and Konosu soil, respectively. Significant liberation of ¹⁴CO2 (55.0%) was observed in Konosu soil after 6 weeks of incubation, but it was only 0.7% in Mito soil. NK-049-OH was also degraded to yield almost the same amount of ¹⁴CO2 in Konosu soil as in the case of NK-049. Under shaking (“aerobic”) flooded conditions, ¹⁴CO2 was liberated from Konosu soil treated with ¹⁴C-NK-049 as under static conditions but little accumulation of NK-049-OH was observed. Microbial metabolites obtained by an isolated microorganism were common with those found in the soil except 3,3′-dimethyl-4-methoxybenzhydrol. © 1980, Pesticide Science Society of Japan. All rights reserved.

Carbon 14-labeled NK-049 was readily metabolized in rice plant tissues. Acetone-chloroform extractable radiocarbon decreased gradually as time lapsed, while unextractable radiocarbon increased without considerable accumulation of water soluble radiocarbon. The most dominant compound in acetone-chloroform extracts was identified as intact NK-049 throughout the experiment. Oxidized NK-049 at 3 or 3’-CH3 group, 4-desmethyl-NK-049 and reduced NK-049 at carbonyl group were also identified though in small amount. Little amounts of radioactive residues were found in 130-day old mature rice plants treated with 14C-NK-049 and, they were very little especially in rice grains. The result indicates that NK-049 itself does not accumulate in the rice grains. © 1979, Pesticide Science Society of Japan. All rights reserved.

Effects of 3,3′-dimethyl-4-methoxybenzophenone (NK-049) on the biosynthesis of photosynthetic pigments in higher plant leaves were studied under different light conditions and the following results were obtained: 1) NK-049 completely inhibited the accumulation of both chlorophylls and carotenoids under strong light to yield white seedlings, while an appreciable amount of chlorophylls and carotenoids were accumulated under weak light, which were decomposed rapidly on exposure of the pale green leaves to strong light. 2) Accumulation of protochlorophyllide and its photoconversion to chlorophyllide a in etiolated leaves were not influenced by NK-049, whereas the carotenoid accumulation was strongly inhibited in darkness as well as in the light. 3) Some intermediates involved in the biosynthesis of β-carotene were accumulated in the dark-grown or dim light-grown seedlings. 4) It was concluded that NK-049 specifically inhibits the dehydrogenation process in carotene biosynthesis, which leads to the photodecomposition of chlorophylls under strong light to result in chlorosis. © 1977, Pesticide Science Society of Japan. All rights reserved.

抄録 作物中の3,3′-dimethyl-4-methoxybenzophenone (NK-049) の定量に際し, 選択性の高い方法である mass fragmentography (MF) の応用を試み, レタス, にんじん, かんしょ中のNK-049をECDと同感度で, より選択的に定量する方法を確立した. 最小検出量は, 0.004ppmであり, 平均回収率は, 83～92%であった.

3, 3′-Dimethyl-4-methoxybenzophenone (NK-049) labeled with carbon-14 at the carbonyl carbon was administered orally to female wister rats at the dosage of 500mg per kg. Carbon-14 absorbed from gastrointestinal tract was rapidly distributed into various tissues. The radiocarbon in the tissue was rapidly excreted into feces and urine; 24hr after the administration, 59.38% and 36.15% of the carbon-14 were excreted in feces and urine, respectively, so that no accumulation of the compounds in animal body was presumed. In feces, 75% of the radiocarbon (46% of the dosed NK-049) was confirmed to be an intact NK-049. Major urinary metabolites were free and conjugated 3, 3′-dimethyl-4-hydroxybenzophenone (9%) and 3′-carboxy-4-hydroxy-3-methylbenzophenone (28%), and free 3′-carboxy-3-hydroxymethyl-4-methoxybenzophenone (23%) and 3-carboxy-4-hydroxy-3′-hydroxymethylbenzophenone (9%). Other oxidized metabolites of NK-049 were found in the urine, such as 3, 3′-dicarboxy-4-methoxybenzophenone, 3′-carboxy-4-hydroxy-3-hydroxy-methylbenzophenone, 4-hydroxy-3′-hydroxymethyl-3-methylbenzophenone, 4-hydroxy-3-hydroxymethyl-3′-methylbenzophenone, 3-carboxy-3′-methyl-4-methoxybenzophenone and 3, 3′-dicarboxy-4-hydroxybenzophenone.

Absorption, translocation and metabolism of 3,3’-dimethyl-4-methoxybenzo-phenone (NK-049) applied to rice and barnyardgrass were examined to elucidate its selective herbicidal action between the two plants. Marked differences were observed in the rates and amounts of absorption and translocation between the rice (tolerant) and barnyardgrass (susceptible) plants. When applied on leaf surface, NK-049 readily penetrated into the leaf of barnyardgrass, while in rice, the chemical was slowly absorbed. Translocation both upward and downward from the treated zone through leaf veins were slight in both plants. When applied to roots by dipping the roots in NK-049 solution, the chemical was absorbed much more by barnyardgrass as compared with by rice and readily translocated to aerial parts. When ap-aplied to intact seeds, NK-049 was absorbed more rapidly by barynardgrass on seed weight basis, while on seed number basis rice seeds absorbed much more NK-049 than barnyardgrass seeds. Radioactivity once absorbed by seeds was translocated to the first leaves in the seedlings of both rice and barnyardgrass, but the amount of translocated radioactivity was much greater in barnyardgrass than in rice. No appreciable difference was found in the metabolism of NK-049 between the two plants. It was suggested that one of the main factors for the selective action of NK-049 is the differences in the rate and amount of absorption and translocation of the chemical between rice and barnyardgrass. Carotenoid formation in barnyardgrass was strongly inhibited by NK-049, whereas that in rice was not affected at all. It was suggested that the susceptibility of the carotenoid-biosynthesis systems of the two plants to NK-049 were greatly different from each other and this difference contributes to the selective herbicidal action of the chemical. © 1978, Pesticide Science Society of Japan. All rights reserved.

Thiocarbamate sulfoxides, which are the active forms of thiocarbamate herbicides, are quickly conjugated with glutathione and decomposed in soil. To achieve more potent and stable herbicidal activity, we previously developed a 5-([(2,6-difluorophenyl)methoxy] methyl)-5-methyl derivative, which has a 4,5-dihydro-1,2-oxazole ring in place of the thiocarbamate to prevent conjugation and decomposition. Although the derivative showed pre-emergence herbicidal activity under flooded conditions, it displayed no herbicidal activity under upland conditions. In contrast, a 5-(methoxymethyl)-5-methyl derivative showed preemergence herbicidal activity against grass weeds under upland conditions. The aim of this study was to obtain a more potent compound with improved physicochemical properties for use as a pre-emergence upland herbicide via the structural optimization of a 3-([(hetero)aryl]methanesulfonyl)-4,5-dihydro-1,2-oxazole as the core structure. In this way, we have developed the pre-emergence herbicide 3-([5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methanesulfonyl)-5,5- dimethyl-4,5-dihydro-1,2-oxazole, which has been named "pyroxasulfone." This novel compound displayed excellent herbicidal activity against grass and broadleaf weeds under upland conditions with no phytotoxicity against crops.

Based on the commercial insecticide chlorantraniliprole, a series of novel N-pyridylpyrazole derivatives containing 1,2,3-triazole moieties were designed and synthesized via Huisgen cycloaddition reaction. The insecticidal activities of the new compounds against the oriental armyworm (Mythimna separata) were evaluated, of which compound Ib with an N-isopropyl anthranilic amide moiety displayed 100% larvicidal activities against Mythimna separata at a concentration of 10 mg/L. Moreover, the fungicidal activities of some target compounds in vitro against five fungi at 50 μg/mL indicated that some compounds exhibited moderate fungicidal activities.

Eight N-(3-(2,4-dichlorophenyl)-5-methylisoxazol-4-ylcarbonyl]-N'-(4,6-disubstituted pyrimidin-2-yl)thioureas and eight 5,7-disubstituted-2-[3-(2,4-dichlorophenyl)-5-methyl isoxazol-4-ylcarbonylimino]-2H-1,2,4-thiadiazolo(2,3-alpha]pyrimidines were synthesized by multi-step reactions in yields of 50-85%. The structures of the target compounds were confirmed by IR, H-1 NMR spectra and elemental analyses. Phytotoxic activities against Echinochloa crus-galli L., Digitaria ciliaris L., Brassica napus L. and Chenopodium serotinum L. were evaluated by the culture dish method. Preliminary bioassay results indicated that some target compounds exhibited good phytotoxic activity at a dose of 100 mg/L, with an inhibitory rate of 76.0-85.6% on root growth, even higher than the control herbicide, fenoxaprop-P-ethyl. (C) Pesticide Science Society of Japan

A series of 5-substituted 1,2,4-oxadiazoles and 1,2,4-thiadiazoles were prepared as muscarinic acetylcholine receptor agonists and evaluated for their insecticidal activity. These derivatives were synthesized through sequential reactions consisting of the condensation of pyridinecarboamides or pyridinecarbothioamides with N,N-dimethylacetamide dimethyl acetal, cyclization with hydroxylamine, quaternization by alkyl halide and reaction with sodium borohydride. All 1,2,4-oxadiazoles and 1,2,4-thiadiazoles synthesized were evaluated for insecticidal activity and their structure-activity relationships are discussed. It was discovered that many compounds were active against representative insects such as Nilaparvata lugens, Nephotettix cincticeps and Aphis craccivora. In particular, it was also found that 3-pyridyl-substituted derivatives of 1,2,4-oxadiazole and 1,2,4-thiadiazole exhibited good insecticidal activity against all the insects tested. Among the compounds evaluated, 3-methyl-5(1,2,5,6-tetrahydropyridin-3-yl)-1,2,4-thiadiazole (9m-2) showed the highest activity against Nilaparvata lugens, and provided a high level of activity against the imidacloprid-resistant strain. Based on the preliminary binding assay using the binding inhibition of mAChR antagonist [(3)H]NMS to the nerve-cord membranes as an index of the binding activity, 9m-2 exhibited a range of potencies for the insect muscarinic receptor. (C) Pesticide Science Society of Japan

A series of novel 5-chloro-3-fluorophenoxypyridines with a 1,3,4-oxadiazole ring bearing a thioether moiety was synthesized and their herbicidal activity against some graminaceous plants and crop safety were examined. Target compounds were prepared through S-substitution reaction of 5-mercapto-1,3,4-oxadiazole analogs, which were synthesized by the reaction of 2-propynyl (R)-2-[4-(5-chloro-3-fluoro-pyridin-2-yloxy)-phenoxy]propionate with hydrazine hydrate and the subsequent reaction with carbon disulfide. The newer 3,5-dihalophenoxypyridines and the intermediate, 5-chloro-3-fluoro-2-{4-[(R)-1-(5-mercapto-1,3,4-oxadiazol-2-yl)ethoxy]phenoxy}pyridine, were characterized using 1H NMR, 13C NMR, IR spectroscopy and elemental analysis. Almost all 5-chloro-3-fluorophenoxypyridines showed a moderate to high level of activity against all weeds tested at 125 g/ha application. In particular, 5-chloro-3-fluoro-2-(4-{(R)-1-[5-(2-propynylthio)-1,3,4-oxadiazol-2-yl]ethoxy}phenoxy)pyridine exhibited potent activity without crop injury.

1-aryloxyaceto-3-(5-ary1-1,3,4-oxadiazol-2-yl)-thioureas を五塩化リン存在下で閉環し, 数種の2-aryl-5-aryloxymethyl-1,3,4-oxadiazolo[3,2-a]-s-triazin-7-thiones を合成した. これらの化合物のA. niger とH. oryzae に対する抗菌活性試験結果から化学構造と活性との関連性について検討した.

Eighteen novel compounds of 2,5-disubstituted-1,3,4-oxadiazoles con-taining benzimidazole moiety were synthesized from 1H-benzimidazole-2-carbohydrazide, carbon disulfide and alkyl halide or benzyl halide by multi-step reactions. The structures of the target compounds were con-firmed by IR, 1H-NMR spectra and elemental analyses. Preliminary anti-fungal activities against Botrytis cinerea and Sclerotinia sclerotiorum were also evaluated by the mycelium growth rate method, and the results in-dicated that many target compounds possess excellent antifungal activ-ity, even higher than the control fungicide (carbendazim).

A series of penta-1,4-diene-3-one oxime ether derivatives were synthesized, and their antiviral and antifungal activities were evaluated. Bioactivity evaluations showed that most target compounds had significant antiviral effects against tobacco mosaic virus (TMV). Among them, (1E,3Z,4E)-1-(4-(benzyloxy)phenyl)-5-(furan-2-yl)penta-1,4-dien-3-one O-(3-fluorobenzyl) oxime (5e) was found to have good curative activity against TMV, with an inhibition rate of 64.6%, which was better than that of ribavirin (45.2%). (1E,3Z,4E)-1-(4-(benzyloxy) phenyl)-5-(furan-2-yl)penta-1,4-dien-3-one O-((6-chloropyridin-3-yl)methyl) oxime (5d) had a remarkable protective effect against TMV, with an inhibitory rate of 66.9%, which was better than that of ribavirin (61.8%). The inhibitory rate of (1E,3Z,4E)-1-(2-(benzyloxy)phenyl)-5-(furan-2-yl)penta-1,4-dien-3-one O-(4-chlorobenzyl) oxime(5m) in inactivation activity against TMV was 87.0%, which was better than that of ribavirin (77.9%). Further molecular docking studies indicated that compound 5m shows strong binding affinities toward the coat protein of tobacco mosaic virus. This result indicates that penta-1,4-diene-3-one oxime ether derivatives can play a significant role in discovering new antiviral agents.