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.     

Quantitative structure-activity analysis of larvicidal 1-(substituted benzoyl)-2-benzoyl-1-tert-butylhydrazines against Chilo suppressalis

The larvicidal activity of a number of 1-(substituted benzoyl)-2-benzoyl–1 -ten-butylhydrazines against the rice stem borer (Chilo suppressalis Walk.) was measured. Variations in the activity were examined quantitatively using physico-chemical substituent and molecular parameters and regression analysis. The results indicated that the molecular hydrophobicity and the electron-withdrawing inductive/ field effect of ontho substituents are favourable to larvicidal activity. The bulkiness of substituents at the meta and para positions was unfavourable to activity, substitution at the para position being more unfavourable than that at the meta position in terms of van der Waals' volume. The 2,3–, 2,5- and 2,6-disubstitution patterns were also unfavourable to activity. Reductions in larvicidal activity caused by the 2,6-,- 2,3,5- and 2,3,4,5-substitutions were greater than those induced by the 2,3- and 2,5-disubstitutions. When the sum of contributions from favourable effects is greater than that from unfavourable effects, the larvicidal activity is expected to be superior to that of the unsubstituted compound.     

Synthesis and structure-activity study of fungicidal anilinopyrimidines leading to mepanipyrim (KIF-3535) as an anti-Botrytis agent

A series of 2-anilinopyrimidines was prepared and their fungicidal activities against Botrytis cinerea Pers were examined. The activity fell sharply with any substitution on the anilinobenzene ring. Substituents at the 5-position of the pyrimidine ring greatly reduced the activity. Substituents such as chloro, methoxy, methylamino, methyl or 1-propynyl were well tolerated at the 4- and 6-positions of the pyrimidine ring. Among these substituents, the combination of methyl and 1-propynyl groups was the most favourable. 2-Anilino-4-methyl-6-(1-propynyl)pyrimidine (KIF-3535), which showed excellent activity and no significant phytotoxicity, was finally selected for development and has been given the common name mepanipyrim.     

Heterocyclic Insecticides Acting at the GABA-Gated Chloride Channel: 5-Alkyl-2-arylpyrimidines and -1,3-thiazines

5-tert-Butyl-2-(4-ethynylphenyl)pyrimidine and the corresponding 2,5-disubstituted-4H-1,3-thiazine block the GABA-gated chloride channel at c.20and c.200 nm , respectively, measured as 50% inhibition of the binding of 1-(4-ethynylphenyl)-4-[³H]propyl-2,6,7-trioxabicyclo[2.2.2]octane (4′-ethynyl-4-n-[³H]propylbicycloorthobenzoate; [³H]EBOB) in house fly and mouse brain membranes, and they are also toxic to topically-treated flies with LD₅₀ values of 6–27 μg g⁻¹ alone and 2–6 μg g⁻¹ with piperonyl butoxide (PB) as synergist. In the pyrimidine series, the general pattern of effectiveness of substituents in the 5-position is tert-butyl>isopropyl≈cyclohexyl≈cyclopropyl>methyl, phenyl and 3- and 4-fluorophenyl, and in the 2-position is 4-ethynylphenyl≪4-bromophenyl. These planar pyrimidines and nearly-planar 4H-1,3-thiazines with 2-ethynylphenyl or 2-bromophenyl and 5-tert-butyl or 5-isopropyl substituents are more effective than the corresponding 6H-1,3-thiazine, 6-oxo-1,3-thiazines and 4,6-dioxo-1,3-thiazine examined, but they are less active than the analogous conformationally flexible trans-1,3-dioxanes and -1,3-dithianes. The heterocyclic moiety confers a region of high electron density and positions the 2- and 5-substituents in a linear or parallel relationship for optimal affinity at the receptor. Two observations indicate that the new pyrimidines and thiazines probably act as chloride channel blockers. First, the poisoning signs are identical to those of EBOB in both mice and house flies. Second, each of the pyrimidines, thiazines and dioxanes falls on the same correlation line for inhibition of [³H]EBOB binding and toxicity to house flies (with PB) as that obtained earlier for EBOB analogs, dithianes and polychlorocycloalkanes, suggesting that they all act at the same or closely coupled binding sites in the GABA-gated chloride channel.     

Dimethoxypyrimidines as novel herbicides. Part 4. Quantitative structure–activity relationships of dimethoxypyrimidinyl(thio)salicylic acids

The activity of a number of O-(4,6-dimethoxypyrimidin-2-yl)salicylic acids and their thio analogs inhibiting acetolactate synthase (ALS) preparation was measured. The effects of substituents on the salicylic-benzene ring on the inhibitory activity were analyzed quantitatively with physicochemical substituent parameters. For 6-substituted (thio)salicylic acids, the activity was shown to vary parabolically with the ‘intramolecular’ steric parameter ( E_s ). In addition, the higher steric dimension of substituents in terms of the STERIMOL width or length parameter lowered the activity. The field-inductive electron-withdrawing property of the 6-substituents in terms of the Swain–Lupton–Hansch F was favorable for the activity of salicylic acid series. In 5-substituted salicylic acids, the activity was increased by electron-donating substituents with smaller size. The relationships between ALS inhibitory and herbicidal activities were also analyzed with some weed species. Both pre- and post-emergence activities against barnyard grass, Echinochloa crus-galli, were linearly related to the ALS inhibitory activity after allowing for the hydrophobic factor that may contribute to the transport processes. Those against two broad-leaved weed species, Polygonum convolvulus and Abutilon theophrasti were linearly related to the in-vitro activity with no significant participation of the hydrophobic factor. © 1998 SCI     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 2. Physicochemical substituent effects and neurophysiological and symptomatic activities against American cockroaches

The substituent effects on the symptomatic and neurophysiological activities of a number of substituted benzyl (1R)-trans-chrysanthemates against American cockroaches were quantitatively analyzed using electronic, hydrophobic, and steric parameters. The effects were shown to be highly specific to substituent positions except for those on the neuroblocking activity. Steric effect of substituents represented by van der Waals volume was found to play the most significant role in determining the variation in each activity. Peculiar substituent effects depending upon the bulkiness and position of substituents, which had been observed in the toxicity of this class of compounds, can be rationalized by the present analysis indicating that the optimum van der Waals volume of substituents is largest at the ortho and smallest at the para position.     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 5. Physicochemical substituent factors and neurophysiological effects in knockdown and lethal activities against the house fly

Knockdown and lethal activities of meta- and para-substituted benzyl (1R)-trans-chrysanthemates against the house fly were measured under synergistic conditions using piperonyl butoxide as an inhibitor of oxidative metabolism and NIA 16388 as an inhibitor of hydrolytic degradation. The variations in these activities were quantitatively analyzed in terms of physicochemical substituent effects using electronic, hydrophobic, and steric parameters of the aromatic substituents, and regression analysis. The most significant parameter in determining these activities is the steric bulkiness represented by the van der Waals voluem, the effect of which is highly specific to substituent positions. The substituent effects on knockdown and lethal activities against the house fly are shown to correspond well, respectively, with those on the convulsive and lethal activities against the American cockroach. The relationship between these symptomatic activities against the house fly and the neurophysiological activities determined by using excised nerve cords from American cockroaches were also quantitatively analyzed. Each house fly symptomatic activity was found to be analyzable by a linear combination of the neuroexcitatory and neuroblocking activity indices when the transport factor was separated by using the hydrophobicity parameter.     

Quantitative structure—activity relationships of light-dependent herbicidal 4-pyridone-3-carboxanilides I. Effect of benzene ring substituents at the anilide moiety

A number of substituted 4-pyridone-3-carboxanilide derivatives show various degrees of light-dependent herbicidal activity. The effects of substituents at the anilide moiety on the activity against Echinochloa oryzicola were analysed quantitatively with physicochemical substituent parameters. The activity was shown to vary parabolically with total hydrophobicity (Σπ) of the anilide ring substituents as well as with the steric parameter (E_s) of the ortho-substituents. The E_s parameter for only the bulkier ortho-substituent, with the more negative value, but not for the two, was significant. The effect of substituents at the 1-position was expressible by indicator variables assigned to each 1-substituted series, the physicochemical rationalization being left for future analyses.     

Quantitative structure—activity relationships of light-dependent herbicidal 4-pyridone-3-carboxanilide derivatives II. Substituent effects of anilide and pyridone moieties

The variations in the light-dependent herbicidal activity against Echinochloa oryzicola of a number of 4-pyridone-3-carboxanilides with various substituents on the anilide and pyridone rings have been examined by use of physicochemical substituent parameters and regression analysis. The effects of substituents of the anilide ring were such that the activity was related parabolically not only with the substituent hydrophobicity (π) but also with the steric bulk parameter (E_s) of the bulkier ortho substituent. The effect of substituents at the 1-position of the pyridone ring was analysed with steric(STERIMOL L and B₅) and electronic(γ₁) parameters. That of substituents at the 5-position of the pyridone ring was explained by a parabolic function of a steric (MR) parameter. Analyses of the activity of 105 analogs confirmed that our previous selection of a candidate compound in this series for field trials was indeed appropriate in terms of physicochemical substituent effects.     

嘌呤氧基苯氧丙酸酯的合成及除草活性

以4,6-二氯-5-硝基嘧啶为起始原料,经过还原胺化、取代、醚化等一系列反应,得到11个未见文献报道的嘌呤氧基苯氧丙酸酯类化合物1a~1k,其结构经1H NM R和M S确认。初步生物活性测定表明:在200 mg/L下,所有目标化合物均表现出一定的除草活性,其中化合物1f((R)-2-(4-((9-(4-氯苯)-8-(三氟甲基-9H-嘌呤-6-基)氧)苯氧)丙酸丁酯)和1h((R)-2-(4-((9-(4-氯苯)-8-(三氟甲基-9H-嘌呤-6-基)氧)苯氧)丙酸乙酯)对靶标的抑制率几乎都达到100%。     

Synthesis,spectral properties and insecticidal,acaricidal and ovicidal activities of some O-(1,5-disubstituted- 6-oxo-12H-pyridazin-4-yl) phosphorothioates

A synthesis of O,O-dialkyl, O-alkyl O-2-chloroethyl (or O-2-ethoxyethyl) O-(1,5-disubstituted-6-oxo-1H-pyridazin-4-yl) phosphorothioates is described. Infrared, Raman and ultraviolet spectra of the compounds prepared are interpreted. The wave-numbers of the v(C? C) bands were correlated with substituent constants. Good linear correlations of v(C? O) with σ, σ^F, σ_I and σ_R were observed for compounds containing various substituents in the neighbourhood of the keto group of the pyridazinone ring. The insecticidal, acaricidal and ovicidal activities of O-(ethyl or isopropyl), O-(alkyl, 2-chloroethyl, or 2-ethoxyethyl) O-(5-methoxy-1-methyl-6-oxo-1H- pyridazin-4-yl) phosphorothioates, O-ethyl O-isopropyl O-(5-methoxy-1-substituted-6-oxo-1H-pyridazin-4-yl) phosphorothioates and O-ethyl O-isopropyl O-(1-methyl-5-substitutedd-oxo-1H-pyridazin-4-yl) phosphorothioates are reported together with the toxicity of some of these compounds to rats.     

Synthesis and insecticidal activity of lipophilic amides. Part 4: The effect of substituents on the phenyl group of 6-phenylhexa-2,4-dienamides

Substituted phenylacetaldehydes, made by homologation of the benzaldehydes by Wittig condensation with a methoxymethylene ylid, were condensed under Wadsworth-Emmons conditions to give the substituted N-(2-methylpropyl)-6-phenylhexa-2,4-dienamides. Electron withdrawing substituents favoured the formation of the unwanted 3,5-diene isomer. Insecticidal activity was lowered by most substituents examined, but was retained or even enhanced by halogen atoms at the m- or p-positions. At the m-position, activity decreased as size of halogen increased.     

Synthesis and insecticidal activity of 3-(haloalkyl-1,3-dienyl)-2,2-dimethylcyclopropanecarboxylates

New 2,2-dimethylcyclopropanecarboxylic acids bearing halogenated 1,3-alkadienyl substituents at position 3 of the cyclopropane ring were synthesised and the insecticidial activities of their 3-phenoxybenzyl and α-cyano-3-phenoxybenzyl esters against housefly (Musca domestica), Colorado potato beetle (Leptinotarsa decemlineata) and Egyptian cotton leafworm (Spodoptera littoralis) were determined. The activity of these compounds varied according to the relative position of the halogen substituents on the diene chain. The observed changes of activity with the structure of the side chain are discussed in terms of the coplanarity of the conjugated double bonds.     

Insecticidal activity of the pyrethrins and related compounds X 5-benzyl-3-furylmethyl 2,2-dimethyicyclopropanecarboxylates with ethylenic substituents at position 3 on the cyclopropane ring

The insecticidal activities against houseflies (Musca domestica L.) and mustard beetles (Phaedon cochleariae Fab.) of the chrysanthemate bioresmethrin, and of 31 related 5-benzyl-3-furylmethyl 2,2-dimethylcyclopropanecarboxylates with alkenyl, alkadienyl or alkoxycarbonylalkenyl substituents at position 3 of the cyclopropane ring are compared to determine the relative influence of the isobutenyl sidechain (as in chrysanthemates) and of the other side chains. Several substituents, in particular (E)- or (Z)-butadienyl or -pentadienyl, give considerably greater activity than isobutenyl but alkoxycarbonyl compounds are less potent.     

Structure–Activity Relationships of Herbicidal Aryltriazolinones

A series of substituted aryltriazolinones, known to inhibit protoporphyrinogen oxidase, were prepared and their structure–activity requirements at positions 4 and 5 of the aromatic ring investigated. A QSAR equation obtained for substituents at the 5 position identified the hydrophobicity term π and the Sterimol minimum width B₁ as the two parameters affecting in-vitro biological activity. Greenhouse pre-emergence activity correlated with in-vitro activity and the hydrophobicity term π of the substituent at that position. It was found that the phenoxy-4-oxyacetate group at aromatic position 5 was an outlier and had to be considered separately. SAR analysis of substituents at aromatic position 4 revealed that two different models were required to explain all observed substituent effects. In the first model, where the 5 position was occupied by hydrogen, the 4-chlorobenzyloxy group at aromatic position 4 gave the best compound. The second model, where the 5 position of the aromatic ring was occupied by a group other than hydrogen, resulted in a QSAR equation, previously derived, which links substituent effects at position 4 with π and with the electronic para inductive term F_p. In this model the chloro group provides optimum biological activity. The need to separate the aryltriazolinone herbicides into several different classes in order to explain their substituent effects at aromatic positions 4 and 5 could be rationalized if more than one binding conformation, within the same binding site, is possible. © 1997 SCI     

2-anilino-3-methylbutyrates and 2-(isoindolin-2-yl)-3-methylbutyrates,two novel groups of synthetic pyrethroid esters not containing a cyclopropane ring

A new series of substituted 2-anilino-3-methylbutyrates has been prepared; bioassay data for these compounds on Heliothis virescens, Musca domestica, Aphis fabae and Tetranychus urticae are presented and discussed. Some unexpected relationships were observed between the nature of the substituents and the biological activity. Increases in foliar stability were noted with certain substitution patterns. Both α-cyano-3-phenoxybenzyl 3-methyl-2-(α, α, α,2-tetrafluoro-p-toluidino)butyrate and the corresponding 2-(2-chloro-α, α, α-trifluoro-p-toluidino)-3-methylbutyrate showed good stability in air and light, and exhibited biological activities of a similar nature and potency to those of previously known synthetic pyrethroids. Esters of the (R)-2- anilino-3-methylbutyric acids are far more active than those prepared from the (S)-enantiomers. The (R)-configuration at C-2 in these acids is sterically equivalent to the active absolute configuration at the chiral carbon α to the carboxylate group in both the permethrin and the fenvalerate types of pyrethroids. A new class of insecticidal 2-(isoindolin-2-yl)alkanoates is also reported. In this series the most biologically active analogue was α-cyano-3-phenoxybenzyl 3-methyl-2-(4,5,6,7-tetrafluoroisoindolin-2-yl)butyrate. These esters were considerably less stable than the anilino analogues on exposure to air and light.     

Synthesis and bioactivity of some fluorine-containing benzoyl arylureas. Part I: Insecticidal-acaricidal products in which the aryl group bears a trifluoromethyl-substituted alkyl or alkenyl side chain

This paper reports the synthesis and the biological activity of benzoyl arylureas in which the aryl group bears a trifluoromethyl-substitiited alkyl or alkenyl side chain, R. The activity of these compounds has been evaluated on larvae of S. littoralis, A. aegypti, L. decemlineata and on the eggs of T. urticae. In general: (1) the optimum insecticidal activities are achieved when the substituents on the benzoyl moiety, R₁, and R₂, are 2,6-difluoro, the substituents on the aryl moiety, R₃, are 3,5-dichloro and R₁, is 4-(? CH?C(CI)CF₃); (2) the best acaricidal activity is shown when R₁, is 2-CI, R₂, and R₃, are hydrogen atoms and R₁, is 4-(? CH₂CH₂CH(CI)CF₃); (3) the best overall activity is displayed when R₁, is 2-CI, R₂ is hydrogen, R₃ is 3-chloro and R₁ is 4-(? CH₂CH₂CF₃).     

Synthesis and insecticidal and acaricidal activity of new N-(α-substituted phenoxybenzyl)-4-pyrimidinamines

A new class of insecticides and acaricides containing N-(α-substituted phenoxybenzyl)-4-pyrimidinamines as core structure were synthesized and their insecticidal and acaricidal potencies assessed. Among these, both the N-(3 or 4-phenoxybenzyl)-4-pyrimidinamine showed remarkable activity against diamondback moth, Plutella xylostella L., brown rice planthopper, Nilaparvata lugens (Stal) and two-spotted spider mite, Tetranychus urticae Koch. The potency of the new pyrimidinamines was particularly increased when a methyl, ethyl, iso-propyl, or cyclopropyl group was introduced at the α-position of benzyl moiety and it was evident that a single (+) optical isomer is more active than its antipode. Structure-activity relationships are discussed.     

Synthesis and insecticidal/acaricidal activity of novel 3‐(2,4,6‐trisubstituted phenyl)uracil derivatives

A series of novel 3‐(2,4,6‐trisubstituted phenyl)uracil derivatives has been synthesised and assayed for insecticidal/acaricidal activity. The assay indicated certain requirements for optimal insecticidal activity, which can be summarised as follows: (a) the substituents on the phenyl ring should possess hydrophobicity and electron‐withdrawing properties, and the sum of their volumes determines the level of activity; (b) the substituent at the 6‐position on the uracil ring should also possess electron‐withdrawing properties and hydrophobicity, together with the correct volume; (c) the 1‐position on the uracil ring should be unsubstituted for activity against Nephotettix cincticeps and Epilachna vigintioctopunctata, but substituents with length C3 to C4 may be optimal for activity against Tetranychus urticae; (d) certain substituents at the 5‐position of the uracil ring give activity against E vigintioctopunctata and T urticae, but not against N cincticeps; (e) a thiocarbonyl group at the 2‐position of the uracil ring is less effective than a carbonyl group. Of the compounds assayed, 3‐(2,6‐dichloro‐4‐trifluoromethylphenyl)‐6‐trifluoromethyluracil showed high activity against all the species assayed. © 2000 Society of Chemical Industry