The pyrethrins and related compounds. Part XXII. Preparation of isomeric cyano-substituted 3-phenoxybenzyl esters

Preparation of 3-phenoxybenzyl chrysanthemates and their dihalovinyl analogues substituted with a cyano group at the 2-, 6-, (R)-α-, or (S)-α- positions is described. The (R)- and (S)- isomers of α-cyano-3-phenoxybenzyl esters of 2,2-difluoro-, -dichloro-, and -dibromo-vinyl analogues of cis- and trans- chrysanthemic acid are separated chromatographically, as are the separate pairs of enantiomers of fenvalerate, (RS)-α- cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate. An optically active ester of α-cyano-3-phenoxybenzyl alcohol (obtained using D -oxynitrilase) with 2,2,3,3-tetramethylcyclopropanecarboxylic acid is synthesised.     

Metabolism of the cis- and trans-isomers of cypermethrin in mice

Metabolism in mice of the separated cis- and trans-isomers of the pyrethroid insecticide cypermethrin (NRDC 149), (RS)-α-cyano-3-phenoxybenzyl (1RS)-cis, trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate, was investigated in each case with preparations that were ¹⁴C-labelled in the benzyl and cyclopropyl moieties. Radioactivity from the trans-isomer was mainly excreted in the urine and that from the cis-isomer in the faeces. Elimination of both isomers was rapid except for a small portion (approximately 2%) of the cis-isomer which was released from the fat with a half-life of approximately 13 days. Metabolism of cypermethrin occurred mainly by ester cleavage and elimination of the cis- and trans-3-(2,2-dichlorovinyl)-2,2-dimethyl- cyclopropanecarboxylic acid moieties as glucuronide conjugates. The α-cyano-3-phenoxybenzyl alcohol released by ester cleavage was mainly converted to 3-phenoxy-benzoic acid which was partly eliminated unchanged, partly conjugated with aminoacids (mainly taurine) and glucuronic acid, and partly oxidised to 3-(4-hydroxyphenoxy) benzoic acid which was excreted as the sulphate conjugate. Metabolites retaining the ester linkage were formed by hydroxylation at various sites in the molecule with more hydroxylation of the cis- than of the trans-isomer occurring.     

The uptake of metabolites of permethrin by plants grown in soil treated with [14C]permethrin

Sugar beet, wheat, lettuce and cotton were grown in soil treated with [¹⁴C]permethrin, the crops being sown at intervals of 30, 60 and 120 days after treatment of the soil. The uptake of radioactive residues into these crops was measured. Low radioactive residues (up to 0.86 μg g^?1) were detected in the mature plants sown 30 days after soil treatment, and this uptake declined significantly as the interval between soil treatment and sowing increased. Metabolites derived from the acid moiety of the permethrin molecule were shown to constitute the greater part of the residue transferring from the soil to the crops. (1RS)-cis- and (1RS)-trans-3-(2,2-dichlorovinyl)- 2,2-dimethylcyclopropanecarboxylic acid and 3-(2,2-dichlorovinyl)-1-methylcyclopropane-1,2-dicarboxylic acid were identified as the major acidic metabolites. The latter compound is a metabolite of permethrin which has not previously been identified in soil or plants.     

Actions of pyrethroid insecticides on insect axonal sodium channels

The actions of pyrethroid insecticides were tested on isolated giant axons of the cockroach Periplaneta americana, using oil-gap, single-fibre recording techniques. Current-clamp and voltage-clamp experiments were used to determine the actions of pyrethroids on axonal membrane potentials and ionic currents. Treatment with deltamethrin at micromolar concentrations caused gradual depolarisation of the axon accompanied by a reduction in amplitude of the action potential. This depolarisation was enhanced by an increase in stimulation frequency. Other synthetic pyrethroids: 3,4,5,6-tetrahydrophthalimidomethyl (1RS)-cis-3-[(RS)-2,2-dimethylcyclopropyl]-2,2-dimethylcyclopropanecarboxylate, biopermethrin and its (1S)-enantiomer, (1R)-tetramethrin, S-bioallethrin, bioresmethrin and its (1S)-enantiomer, cismethrin, and 5-benzyl-3-furylmethyl (E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate (RU-15525, ‘Kadethrin’) were investigated. The (1S)-enantiomers were inactive, but all the other pyrethroids tested, apart from deltamethrin, induced prolonged negative (depolarising) after-potentials. All the treatments with the active pyrethroids resulted in the appearance of a voltage and time-dependent ‘maintained’ sodium conductance. The duration of this ‘slow’ conductance varied considerably depending on the pyrethroid under test. Clearly, the effectiveness of pyrethroids on whole insects is not determined only by the degree to which they directly modify the properties of sodium channels. Nevertheless, voltage-clamp experiments on isolated axons readily permit direct comparison of the actions of different pyrethroids on the sodium channels of insect neurones.     

Effect of the fungicide fenitropan on the metabolism of some higher plants and Fusarium oxysporum

The effect of fenitropan [(1RS, 2RS)-2-nitro-1-phenyltrimethylene di(acetate)], a new fungicide from EGYT Pharmacochemical Works, on the photosynthetic activity, respiration, RNA content and protein synthesis of some higher plants and Fusarium oxysporum, was investigated. The effect on the aminoacylation of tRNAs suggests that fenitropan is an inhibitor of the aminoacyl tRNA ligases accepting aromatic amino acids.     

The pyrethrins and related compounds; Part XXIV: synthesis, 13C-nuclear magnetic resonance spectra and insecticidal activity of cycloalkyl analogues of fenvalerate

Close isosteres of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate], in which cyclopropyl groups replace isopropyl have insecticidal activity close to or greater than the parent compounds, and diminished intravenous toxicity to rats. A direct toxicological relationship of these compounds to fenvalerate itself and to chrysanthemate esters is indicated by the consistently greater activity of esters from one of an enantiomeric pair of acids. Other esters with larger alkyl or cycloalkyl groups, or spiropentane analogues of chrysanthemates are less active insecticides. ¹³C-Nuclear magnetic resonance spectra suggest that in the α-cyanobenzyl esters there is an intramolecular through-space interaction in solution. The relationships between the chemical structures of the compounds synthesised and their relative activities to different insect species and toxicity to rats are discussed.     

Photolysis of flucythrinate

Photolysis of flucythrinate ((RS)-α-cyano-3-phenoxybenzyl (S)-2-(4-difluoromethoxyphenyl)-3-methylbutyrate) in solution (methanol) by UV light (> 290 nm) and as a thin film on glass by exposure to sunlight yields products resulting from ester cleavage. The major product in solution is formed via photo-induced decarboxylation. When thin films are exposed to sunlight, flucythrinate has a half life of 8 days on glass and 3 days on a leaf surface.     

Stereochemical and chiral aspects in the synthesis of 3-(2,2- dihalovinyl)-2,2-dimethylcyclopropanecarboxylic acids

The synthesis of (1RS)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid by dehydrohalogenation of 4,6,6,6-tetrahalohexanoates has been modified to produce stereo-selectively the cis-isomer. A new stereospecific synthesis of cis-3-(2,2-dihalovinyl)-2,2-dimethylcyclopropanecarboxylic acids using a bicyclic lactone and its extension to the preparation of the optically active (1R)-cis acid are described.     

Insecticidal activity of the pyrethrins and related compounds. Part XI. Relative potencies of isomeric cyano-substituted 3-phenoxybenzyl esters

The insecticidal activities to Musca domestica L. and Phaedon cochleariae Fab. of a series of 3-phenoxybenzyl pyrethroid esters with a cyano substituent at the 2-, 6-. (R)-α-, or (S)-α-position are compared with those of the unsubstituted analogues. Only an (S)-α-substituent enhances activity; others diminish or almost eliminate it. (RS)-α-mixtures are generally less active than would be predicted from the potencies of their separate constituents.     

Separation and identification of short-lived free radicals formed by photolysis of the pyrethroid insecticide fenvalerate

Using a spin-trap reagent 3-nitrosodurene (1,2,4,5-tetramethyl-3-nitrosobenzene), the short-lived free radicals generated by ultraviolet irradiation of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] in degassed benzene or dichloromethane, were scavenged as the more stable nitroxide radicals. These radicals were separated by high-performance liquid chromatography and identified individually by electron-spin resonance spectroscopy, as well as by gas chromatography/mass spectrometry. As a result, they were found to be the spin adduct mixtures of the 4-chloro-α-isopropylbenzyl and α-cyano-3-phenoxybenzyl radicals, which are involved in the photo-induced decarboxylation process of fenvalerate. Discrimination of the radicals was also performed by the isotope-labelling method whereby the benzylic proton in the acid moiety was deuteriated. The spin numbers of the nitroxides decreased by about five-fold when photolysis was carried out in oxygenated benzene solution. N-Benzylidene-tert-butylamine N-oxide trapped both radicals but much less efficiently. The nitroxide of the 4-chloro-α-isopropylbenzyl radical was predominant at 25°C or –40°C, but the proportion of the α-cyano-3-phenoxybenzyl nitroxide radical increased at the lower temperature.     

The metabolism of fenvalerate in plants: The conjugation of the acid moiety

The metabolism of the pyrethroid insecticide fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] ( I ), and of its most insecticidal (αS,2S) isomer ( II ), has been examined in cabbage plants grown and treated under laboratory conditions with [¹⁴C]chlorophenyl- and [ring-¹⁴C]benzyllabelled preparations of the two compounds. Both insecticides disappeared from the treated leaves with similar half-lives of approximately 12–14 days; they underwent ester cleavage to a significant extent, together with some hydroxylation at the 2- or 4-position of the phenoxy ring, and hydrolysis of the nitrile group to amide and carboxyl groups. Most of the carboxylic acids and phenols thus produced occurred as glycoside conjugates. In separate experiments, the uptake and metabolism of 2-(4-chlorophenyl)-3-methylbutyric acid ( X ), the acidic half of the molecule, were examined in the laboratory, using abscised leaves of kidney bean, cabbage, cotton, cucumber and tomato plants. The acid X was found to be readily converted, mainly into glucose and 6-O-malonylglucose esters in kidney bean, cabbage and cucumber plants, into glucosylxylose, sophorose and gentiobiose esters in cotton, and into two types of triglucose esters with differing isomerism in tomato. One of the acetyl derivatives of the trisaccharide conjugates was identical with the synthetic deca-acetyl derivative of the [1 → 6]-triglucose ester.     

Disposition kinetics,cytotoxicity and residues of fenvalerate in tissues following oral administration to goats

Disposition kinetics in goats of fenvalerate [(RS)-α-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate] were studied after oral administration at 5 mg kg^?1. The insecticide persisted in blood for up to 48 h. The V_d(area), t_1/2(β), and t_1/2(Ka), of fenvalerate were 12.14 (±0.39) litre kg^?1, 12.25 (±0.25) h and 0.63 (±0.11)h, while the AUC and Cl_B values were respectively 7.35 (±0.39) μg h ml^?1 and 0.68 (±0.04) litre kg^?1 h^?1. The residues in tissues reached a peak four days after insecticide administration and then started to decline. Maximum residue was found in the adrenal gland, followed by liver, kidney and intestine. Both GOT and GPT activities in kidney tissue, but only GPT activities in liver tissue had decreased significantly 4, 8 and 22 days post-administration. The fenvalerate did not produce any significant effects on serum acetylcholinesterase, cholesterol or protein levels in goats. Histopathological examination showed fatty changes in the periphery of lobule, congestion in sinusoid, haemolysis in central vein, necrosis and periportal fibrosis around the central vein of liver, and necrosis in kidney of fenvalerate-treated goats.     

Pyrethroid insecticides derived from substituted biphenyl-3-ylmethanols

The synthesis of a series of mono- and disubstituted biphenyl-3-ylmethyl esters of 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid is described. The bioactivity of these compounds against Spodoptera eridania, Epilachna varivestis, Oncopeltus fasciatus, Acrythosiphon pisum and Tetranychus urticae is presented and discussed. Substitution of fluorine, chlorine and methyl groups in the 2-position of the biphenyl ring generally led to an increase in activity over the unsubstituted parent biphenyl ester. In addition, pyrethroid esters derived from these 2-substituted biphenyl-3-ylmethanols appeared to have a broader spectrum of activity than ‘classical’ pyrethroids. For example, the (1RS)-cis-3-(2,2-dichlorovinyl)-2, 2-dimethylcyclopro-panecarboxylic acid ester of 2-methylbiphenyl-3-ylmethanol was acaricidal, while maintaining a level of activity against other insects that was equal to or greater than cis-permethiin. Biological data on other esters of this novel alcohol are also presented.     

A new pyrethroid of high insecticidal activity

New pyrethroids containing heterocyclic rings in the alcohol moieties were synthesised and their insecticidal activities were studied. Of these new pyrethroids, 3-benzylpyrrol-1-ylmethyl (1RS-cis, trans-3(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate was found to be the most effective, having higher activity than permethrin against Musca domestica by a topical application method. In addition, para-substituted analogues of the 3-benzylpyrrol-1-ylmethyl ester were also synthesised to study the substituent effects on insecticidal activities; the residual effects of these compounds against Blattella germanica were also examined.     

Analysis of soils for diclofop-methyl and diclofop

A method is described for the analysis of soils for residues of the herbicide diclofop-methyl, methyl (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propionate, and its breakdown product diclofop, (RS)-2-[4-(2,4-dichlorophenoxy)phenoxy]propionic acid. Diclofop-methyl undergoes hydrolysis in the soil to diclofop, which also has herbicidal activity. A procedure, using a 1% phosphoric acid solution for extraction purposes, has been developed and gives good recoveries of both diclofop-methyl and diclofop at the 0.5 and 0.05 mg kg^?1 levels. After methylation, gas-liquid chromatography with electron-capture detection is used to determine total residue concentrations.     

Toxicology and metabolism of some synthetic pyrethroids in larvae of susceptible and resistant strains of the cattle tick boophilus microplus (Can.)

Larvae of the Malchi and DDT-R pyrethroid-resistant strains of ticks, compared with larvae of the Yeerongpilly (susceptible) strain, exhibited knock-down resistance equally to (1 RS)-cis- and (1 RS)-trans-permethrin but little resistance to either (1 RS)-cis- or (1 RS)-trans-cypermethrin. Kill resistance was higher in Malchi than in DDT-R ticks and more pronounced against the permethrin isomers. The cis-isomers were more potent overall than the trans-isomers. Cypermethrin isomers penetrated more slowly than permethrin isomers, especially into Malchi larvae. Metabolic detoxication, mainly esteratic, was fastest in Malchi larvae, trans-isomers consistently being attacked faster than cis-isomers. The greatei resistance of Malchi ticks is therefore probably due to a combination of these two differences. Dual mechanisms of the toxic action of pyrethroids are discussed.     

Absorption and metabolism of permethrin and cypermethrin in the cockroach and the cotton-leafworm larvae

Permethrin was metabolised by attack at the ester bond, in vivo by adult cockroaches, Periplaneta americana and in vitro by esterase preparations. Metabolites retaining the ester linkage could not be detected. In all cases, the (1RS)-trans-isomer (transpermethrin) was more labile than the (1RS)-cis-isomer. Cypermethrin was metabolised at one-fifth the rate for permethrin. In-vitro and in-vivo studies with synergists indicated that cleavage of the ester bond in permethrin can be both oxidative for the (1RS)-cis-isomer and hydrolytic for the (1RS)-trans-isomer. The penetration of permethrin through the cuticle of the cockroach was significantly greater than that of cypermethrin. The penetration and metabolism of permethrin and cypermethrin in sixth-instar larvae of susceptible and resistant strains of the Egyptian cotton-leafworm, Spodoptera littoralis, were studied as possible factors in resistance. No significant differences were found. It is suggested that the major resistance factor to permethrin in S. littoralis is probably non-metabolic.     

Effect of adjuvants on the performance of the new cereal fungicide,metconazole. I glasshouse trials

Metconazole, (1RS, 5RS; 1RS, 5SR)-5-(4-chlorobenzyl)-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol, is a highly active fungicide, in particular controlling seed-borne and foliar diseases of cereals, such as wheat (Triticum aestivum L.) and barley (Hordeum vulgare L.). In order to maximize its foliar activity, an experimental survey of some types of surfactants and an emulsifiable oil was undertaken. Two types of metconazole formulation were investigated using a biological assay involving the therapeutic control of two diseases (Erysiphe graminis DC f. sp. tritici Marchal and Leptosphaeria nodorum Muell.) of wheat. Enhancements of activity by ?Genapol’? C12/C14 alcohol ethoxylates of an emulsifiable concentrate (ECM) formulation of metconazole were approximately three- to four-fold. For its, initially, less active suspension concentrate (SCM) formulation, enhancements were around 35-fold, so that with these adjuvants the two formulations were of similar activity. The enhancement ability of these ?Genapol’? surfactants was optimal at lower (5–10 moles) ethylene oxide content. These analogues induced marginally better enhancements of activity than members of a range of nonylphenol ethoxylates (?Arkopal’?), and emulsifiable paraffinic/naphthenic oil (HVI 60E) and a castor oil ethoxylate (?Atlas’? G1281) but were equivalent to a similar series of alcohol ethoxylates (?Dobanol’?) from another source. Varying the alkyl chain length between C₉-C₁₁ and C₁₄-C₁₅ in the ?Dobanol’? series had little effect on their high enhancements of metconazole activity. It was determined from trials varying the application rate of the best alcohol ethoxylates that application rates of 1–1.5 kg ha^?1 were required for maximum activity. This implied the use of high adjuvant/metconazole ratios in one-pack adjuvant-containing formulations. A range of soluble liquid (SL) formulations were prepared with either ?Dobanol’? 23–6.5 or ?Dobanol’? 91-6/metconazole ratios varying from 5:1 to 15:1. There were found to be highly active and were recommended for field testing.     

Quantitative structure-activity relationships of pyrethroid insecticides

The structure-activity relationships of two congeneric series of pyrethroid insecticides, the methylbenzyl (1RS)-cis,trans-chrysanthemates tested against Musca domestica (houseflies) and Phaedon cochleariae (mustard beetles), and the (E)-4-aryl-3-chlorobut-2-enyl chrysanthemates and their corresponding 2,2,3,3-tetramethylcyclo-propanecarboxylates tested against M. domestica only, have been examined using multiple regression analyses and substituent constants. With M. domestica, different optimum partition values (π) were indicated for knockdown and toxicity; with P. cochleariae, an optimum π value for toxicity, similar to that for M. domestica, was obtained 24 h after application, but at later times the more lipophilic compounds were more effective. For the methylbenzyl chrysanthemates, a steric constraint associated with 3,5-dimethyl substitution reduced toxicity approximately five-fold. The influence on toxicity of geometrical isomerism and electronic effects are briefly discussed. Differences between the required polarities for knockdown and toxicity are attributed to variations in the binding affinities of pyrethroid molecules at the sites of action.     

The relationship between the Physicochemical properties of pyrethroid insecticides and their speed of neurotoxic action

The rate of onset of pyrethroid-induced depolarisations of the nerve cell membrane in isolated ganglia of the leech Hirudo medicinalis was measured using intracellular recordings. The speed of neurotoxicity of a series of substituted benzyl (1RS)-trans-cyclopropane-1-carboxylates was related to the size of the groups at C3 and C4 of the benzyl ring, the ability of the ring substituents to donate electrons, and the nature of the substituents at the two terminal positions of the vinyl group subtended by the cyclopropane ring. The speed of action was also related to the electronic environment of the protons subtended by the geminal methyl group held trans to the carboxyl group. Compounds, the partition properties of which were sensitive to interactions between the pyrethroid and solvent molecules, tended to act rapidly. There was no simple relationship between the speed of neurotoxic action in isolated leech ganglia and the knockdown potency to mustard beetles.