A number of N-(substituted-aryl)-2-chloropyridine-3-carboxamides were synthesized and their structure-activity relationships studied. A series of compounds showed potent fungicidal activity against grey mold caused by Botrytis cinerea, in addition to rice sheath blight caused by Rhizoctonia solani. In the case of fungicidal activity against grey mold, derivatives having alkyl groups at the ortho-position in the anilino moiety exhibited high activity. N-(Indan-4-yl) carboxamides having alkyl groups at the 3-position showed particularly high activity. The introduction of heteroatoms into the ring reduced the activity. The fungicidal activities of miscellaneous fused aryl derivatives were elevated as the length of alkyl substituents increased. With respect to activity against rice sheath blight, anilides substituted by alkoxy or alkyl groups at the meta-position showed high activity. Indanyl or miscellaneous fused aryl carboxamides having alkyl groups at the 1-position demonstrated notably high activity. Among the compounds of the series, N-(1, 1, 3-trimethylindan-4-yl)-2-chloropyridine-3-carboxamide (BC723) had the most potent activity against both diseases.

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Soil bacteria producing aryl acylamidases extracellularly were isolated by a convenient method capable of detecting the activity directly on an agar plate where colonies developed, by overlaying successively the agar layers containing substrate acetanilide (AAN) and reagents for coloration by aniline (AN) released. The detection ratio of colonies producing the enzymes was 6% in Bouillon medium and 13% in a minimal medium containing AAN as a sole carbon source. In a liquid culture of the most active bacterium, A-1, 69% of the activity existed in the supernatant of broth and 29% was remained with sonicated cell debris. The activity of this extracellular enzyme (s) remarkably increased under preincubation with AAN. Among the extracellular enzymes from active colonies isolated with Bouillon medium and the minimal medium, 60% and 42% of the enzymes, respectively, were highly activated by AAN. This substrate activation, at least by AAN, seemed fairly general for extracellular aryl acylamidases originated from soil bacteria.

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Effects of N-cyanomethyl-2-chloroisonicotinamide (NCI) on respiration, lipid metabolism, polyamine biosynthetic enzymes, and activities of lipoxigenase (LOX) and peroxidase (POX) in rice plants were investigated in terms of resistance against rice blast disease. The respiration in glycolytic process which supplies NADPH was stimulated by submerged application of NCI in compatible plants inoculated with P. oryzae, whereas the respiration related to TCA cycle which is represented by oxidation of acetate was not affected. Incorporation of [2-¹⁴C] acetate into lipids was enhanced remarkably in the NCI-treated, inoculated plants at 36hr after infection. Activities of ornithine decarboxylase (ODC) and S-adenosyl-methionine decarboxylase (SAMDC) were suppressed about 50% in inoculated plants, whereas such suppression was not observed in NCI treated plants. No remarkable change in ODC and SAMDC activities may account for steady resistance of the plants against the invading pathogens. The activities of LOX and POX were significantly augmented by infection of NCI-treated plants, which appeared to be shifted to an incompatible variety. These results indicate that NCI has a priming effect related to the resistant reaction of rice plants to the pathogen.

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Injection of cAMP, cGMP and dbcAMP (50, 250 and 500μg) into decapitated Bombyx mori females induced pheromone production in a dose-dependent manner. Among these cyclic nucleotides, cAMP proved to be the most active. Under in vitro conditions, however, cyclic nucleotides did not stimulate pheromone production even in a wide range of concentrations (1μM-10mM). Likewise, MIX or forskolin, or both (10μM-1mM) also failed to stimulate pheromone glands to produce bombykol, whereas, MIX (50μM) enhanced the action of Bom-PBAN-I and increased bombykol production by 30-60%. In addition, both MIX (100μM) and forskolin (100μM) enhanced the action of calcium ionophore in bombykol production by two to three times. The action of PBAN on in vitro pheromone production was inhibited in a dose-dependent manner by adding lanthanium ion (100μM-10mM) into the medium. Present results provide some evidences for the requirement of calcium ion influx, suggesting the involvement of calcium ion or cAMP, or both in the mode of action of PBAN in the pheromone glands of B. mori.

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Cultured rice-plant cells treated with N-cyanomethyl-2-chloro-isonicotinamide (NCI) and supplied with blast fungus hyphal component (BFHC) augmentated phenylalanine ammonia-lyase (PAL) more than those given BFHC alone. Enhancement of phosphatidylinositol (PI) metabolism and increase of ethylene production preceded increase of PAL activity. The enhancement of PI metabolism and the increase of ethylene production always occurred earlier in NCI-pretreated, stimulated cells than in NCI-nonpretreated, stimulated cells. Ethylene was produced in large amount from [U-¹⁴C] glutamic acid in the stimulated cells but only in trace amount from L-[U-¹⁴C] methionine, which suggested that the glutamic acid pathway mainly contributed to ethylene biosynthesis in the cells. Augmentation of PAL activity by BFHC was inhibited by the specific calmodulin inhibitor W-7, and Ca²⁺-binding proteins such as calmoduline appeared to mediate biosignal transduction from membrane receptors to cellular effector systems. The rate of PAL-activity inhibition by W-7 was compensated to one half in the NCI-pretreated cells. These results suggest that NCI accelerate the operation of biosignal transduction in an early stage of elicitation process and promote PAL activation in the stimulated cells.

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A series of sulfonylamidines with a cleaved type of thiadiazine ring between the N-4 and C-benzene bond in 1, 2, 4-benzothiadiazine 1, 1-dioxide were prepared, and their rice-blast control activity was examined. Some of these compounds exhibited good activity by foliar application. Substituents appeared to be important for the activity. The most effective was N-(C-Diethylamino-n-hexylmethylene)-p-toluenesulfonamide (24), the activity of which was stronger than that of O, O-diisopropyl S-benzyl phosphorothiolate (IBP).

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[in Japanese]

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The authors, with the intention of exploring an insecticide bearing a new mechanism other than nervous system inhibition and hence possible low mammalian-toxicity, focused as a lead on the biological profile of the benzoylphenylurea (BPU) compounds during their research works and finally selected chlorfluazuron which was marketted against lepidopterous pests of vegetables and fruit trees in 1988 as Atabron® and also as Helix® and Aim® in Japan and foreign countries, respectively. At the time of the commencement of the exploration, the consideration was put on the following three attempts: 1. setting up of a new bio-assay system eligible for the detection of slow larvicidal activity specific to the BPU IGRs, 2. diversification of trifluoromethylpyridine intermediate already industrialized through the development of fluazifop-butyl, and 3. examination of utilization of a new chemorational design based on the trifluoromethylpyridine synthons as a building block for the molecule set-up. Chlorfluazuron selected among the closely related pyridyloxyphenyl-benzoylureas showed far surpassing insecticidal activity over the lead diflubenzuron against specific target insects such as lepidoptera, diptera and orthoptera at their larval stages by chitin biosynthesis inhibition mechanism. The detailed history before and after the exploration, larvicidal activity and selectivity, quantitative structure-activity relations, synthesis, toxicology etc. with respect to chlorfluazuron are discussed.

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Organophosphorus insecticides are one of the largest groups of pesticides and most of them have one or two sulfur directly connected with phosphorus atom. Thiono or thiolothiono types of organophosphorus insecticides exert their insecticidal activity by inhibiting acetylcholinesterase (AChE) after activation. This activation is mediated by the mixed function oxidase (mfo), and thus the reaction is regarded as one of the most important ones. Studies on the origin of oxygen incorporated into the phosphinyl disulfide resulted from peracid oxidation indicated that the occurrence of phosphinyl disulfide was direct evidence for the phosphorus oxythionate intermediate as the initial oxidation product of phosphorothiolothionate compounds. An analytical procedure was developed to derive the unstable phosphinyl disulfide into the stable S-thiomethyl phosphorothiolates. By using this technique, the occurrence of the phosphorus oxythionate intermediate at mfo oxidation became evidenced.Phosphorothionate compounds are often isomerized to the thiolo isomers of higher toxicity by heat or light. The occurrence of such isomerization by mfo system was first indicated. S-Alkyl phosphorothiolates are insecticidal but do not inhibit AChE in vitro. The type of activation was shown to be the production of the unstable sulfoxide which inhibits AChE. Evidences were provided to indicate the involvement of another activated form, the glutathione conjugate of the sulfoxide which inhibits AChE. From a S-alkyl phosphorothiolothionate, the phosphinyl disulfide was obtained by peracid oxidation, which gave the unstable sulfoxide, then its glutathione conjugate, both being the potential activated forms.

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Gas chromatograph-mass spectrometric (GC-MS), high-performance liquid chromatographic (HPLC) and derivatization methods for the pesticide residue analyses have been developed. GC-MS method was applied to multi-residue analyses of organophosphorus pesticides in crops to tentatively identify the pesticide with common fragment ions which provides information on the elemental content and to determine by characteristic fragment ions of each pesticide. The GC-MS method was also applied to determination of various pesticides in river water. HPLC method was used for simultaneous analysis of thioureas in rat plasma, which are toxic to man. This method was based on cleanup by an Extrelut column and determination with wavelength at 240nm, and applied to the analysis of ETU which is a degradation product of fungicide ethylenebis (dithiocarbamate) (EBDC). ETU in crops was able to be determined without extensive cleanup procedure. In addition, the stability of ETU in stored samples before analysis was studied. ETU in certain crops decreased with storage time. When L-cysteine hydrochloride (Cys-HCl) was used as an amendment, the degradation rate of ETU decreased. Cys-HCl also prevented degradation of EBDC to ETU during storage and analysis. For the determination of a guanidino fungicide, guazatine triacetate, a derivatization method was developed. Guazatine triacetate was reacted with hexafluoroacetylacetone (HFAA) to form the bis (trifluoromethyl) pyrimidine derivative. However, very low recoveries were obtained in the analysis of samples such as apple and grape. The phenomenon was due to that guazatine triacetate was strongly bound to fructose which is a constituent in apple and grape. To release the bound, guanidine-HCl was found to be the best reagent. Using these method described above, pesticide residues in crops could be detected at ppb or ppt levels.

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SHIBUYA INDEX (5th Edition) was published in May, 1991 as a joint production of Zen-Noh and Kumiai Chemical Ind. This is the comprehensive index of pesticides which has been edited by the reporter since 1978. The INDEX contains a broad range of information such as common names, code numbers, names of companies, chemical structures, formulation types, safety data, registration status in Japan and/or other countries, application, etc. All known products—whether old or new, with common names or trade names—are listed including those whose chemical structures have been recently published. The total number of products listed in the INDEX is 6755 including 3710 combination products and the total number of names including common names, code numbers and trade names is more than 30, 120. The reporter has been working on this type of study since 1962 and it has been a process of repeated trial and error. The most distinctive features of the INDEX are: (1) all compounds have been grouped by chemical structure. (2) once the chemical structure is clear, it is easy to locate a compound and common name, code number and/or trade name can easily be found. (3) analogous compounds or similar types of combination can be easily found. (4) from the chemical structures described in the INDEX, new ideas may emerge for the future synthesis of new molecules. This report describes the history and details of the study, such as how the INDEX was made, how it can be improved and how to use it.

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[in Japanese]

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[in Japanese]

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[in Japanese]

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[in Japanese]

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In order to investigate toxicological properties of Chloridazon, a number of toxicological studies were carried out with CHLORIDAZON TECH and/or PYRAMIN WP. From these studies, it can be derived that the acute toxicity, subacute toxicity, and long-term toxicity are rather low. Weak or moderate irritant effects on eye and skin were noted, but no skin sensitizing effect was observed. Inhalation risk can be excluded under practical conditions. No adverse effects were observed on reproduction parameters, and no signs of teratogenic effects were noted. Chloridazon was investigated for mutagenic properties in various studies, all three end points of genetic damage covered. In view of these results, Chloridazon can be assessed as not mutagenic. There were no signs of an oncogenic response in any of the tested animals.
Withholding values have been set for the registration at 0.1ppm each on sugar beet and vegetables since April, 1976.
A safety risk for Chloridazon is not to be expected as far as it is used in accordance with the established safe use standard.

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