Synthetic pyrethroids containing a C–C triple bond

The three commercial synthetic pyrethroids containing a carbon–carbon triple bond, α-ethynyl-2-methylpent-2-enyl (1R)-trans-chrysanthemate, (S)-2-methyl-4-oxo-3-(2-propynyl)cyclopent-2-enyl (1R)-trans,cis-chrysanthemate and [2,5-dioxo-3-(2-propynyl)-1-imidazolidinyl]methyl (1R)-trans-chrysanthemate are reviewed with emphasis on their inventive histories. Their chemistry and efficacy are described briefly. The relationship between stereochemistry and the biological activity is also discussed. © 1998 SCI.     

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.     

Green-odour compounds have antifungal activity against the rice blast fungus <Emphasis Type="Italic">Magnaporthe oryzae</Emphasis>

Four green-odour compounds—trans-2-hexenal, cis-3-hexenol, n-hexanal, and cis-3-hexenal—were applied (0.85 μg ml⁻¹ as vapour) to rice plants in laboratory conditions to observe their biological activity against the phytopathogenic fungus Maganporthe oryzae, which causes rice blast disease worldwide. Two compounds, trans-2-hexenal and cis-3-hexenal, showed remarkable disease suppression efficacy (99.7% and 100% suppression, respectively), while n-hexanal had moderate (86.5%) and cis-3-hexenol had weak (20.8%) disease-suppressing effects. Pre-application and post-application of trans-2-hexenal or cis-3-hexenal had slight effects on blast incidence, suggesting that these compounds had direct effects to suppress M. oryzae infection. In fact, trans-2-hexenal and cis-3-hexenal exhibited a growth suppression effect on M. oryzae. Interestingly, these two compounds inhibited appressorium formation at lower concentrations than the growth suppression. Studies on the hypersensitive response (HR)-like reaction and plant β-1,3-glucanase activity in rice plant confirmed that induced resistance was not the major factor involved in the disease suppression mechanism. Results of this study conclusively showed that trans-2-hexenal and cis-3-hexenal possess potent inhibitory activities against the growth and the appressorium formation of M. oryzae and could be used as antifungal agents to significantly reduce M. oryzae infections in rice.     

Increased metabolism of a pyrrolidine urea herbicide in corn by a herbicide antidote

Corn, cotton, and sorghum plants were injured by high rates of 5328 (cis-2,5-dimeihyl-1-pyrrolidinecarboxanilide) when it was applied to the soil surface al planting time. The injury was severe al 35·84 kg/ha (eight times recommended dosage) and in corn resulted in complete inhibition of adventitious root development and reduced shoot and primary and secondary root growth. Treatment of the seeds with 0·5% Protect (1,8-naphthalic anhydride) prior to planting dramatically decreased the injurious effect of 5328 on corn, sorghum, and cotton. Using ¹⁴C-5328 in corn, it was shown that Protect did not alter herbicide uptake. However, the rate of conversion of the herbicide molecule in corn tissue lo water soluble, nonherbicidal metabolites was markedly enhanced in plants grown from Protect-treated seeds.     

Quantification of GST and esterase activities in pyrethrin-resistant mosquitoes using pyrethroid-like fluorescent substrates

Botanical pyrethrins and synthetic pyrethroids are highly potent and environmentally safe insecticides that are used to control a wide range of disease vector and pest arthropods. Unfortunately, resistance to these insecticides has been demonstrated in numerous medically important mosquito species. In this study, adult Culex pipiens sensu lato were captured in agricultural and urban locations in Fresno County, California, and subsequently exposed to a commercial formulation of pyrethrin insecticide by ultra-low-volume spraying. Following insecticide exposure, two pyrethroid-like, fluorescent substrates (4-methyl-2-oxo-2H-chromen-6-yl, cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate (cis-DCVC) and 4-methyl-2-oxo-2H-chromen-6-yl, cis-3-((Z)-2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate (cis-TFMCVC)) and 1-chloro-2,4-dinitrobenzene (CDNB) were used to measure esterase and glutathione S-transferase (GST) activities in surviving mosquitoes. Elevated esterase activity (2.5-fold) was found in surviving urban mosquitoes at 12-h post-pyrethrin exposure (in comparison to non-insecticide-exposed control mosquitoes) when cis-TFMCVC was used as a substrate. Additionally, when CDNB was used as a substrate, 2.8-fold higher GST activity was found. A simple assay was established using our pyrethroid-like, fluorescent substrates that was able to detect low-level esterase activities in homogenates made from individual mosquitoes. The cis-TFMCVC-based assay suggested that esterase activity plays a role in pyrethrin resistance in urban mosquitoes in California.     

Degradation of acylanilide pesticides by Aspergillus niger

Aspergillus niger converts the herbicide 3′-chloro-2-methyl-p-valerotoluidide (solan) to 3′-chloro-4′-methylacetanilide and the fungicide 2,5-dimethylfuran-3-carboxanilide to acetanilide. The metabolites were formed by hydrolysis with an aryl acylamidase, followed by subsequent acetylation resulting in the corresponding acetanilides. Their structures were elucidated by mass spectrometric analysis and confirmed by comparison with synthetic compounds.     

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.     

Stability of cypermethrin and cyfluthrin on wheat in storage

Cypermethrin and cyfluthrin were applied to wheat, which was stored for 52 weeks at 25 or 35°C, and either 12 or 15% moisture content. Total residues and the proportions of the four pairs of enantiomers, cis I [(αR),(1R)-cis + (αS),(1S)-cis], cis II [(αR),(1S)-cis + (αS),(1R)-cis], trans III [(αR),(1R)-trans + (αS),(1S)-trans], and trans IV [(αR),(1S)-trans + (αS),(1R)-trans] for each pyrethroid were determined at five intervals during storage. For all storage conditions, the cis I isomers were the most stable, and the trans IV isomers were the least stable. Calculated half-lives (weeks) for the pairs of enantiomers at 25°C (12% moisture) and 35°C (15% moisture) were: cypermethrin, cis I, 252, 62 and trans IV 66, 27; cyfluthrin, cis I, 114, 52 and trans IV 42, 23. The results suggested that one of the enantiomers of the cypermethrin trans IV pair was degraded faster than the other.     

Metabolism of cisanilide (cis-2,5-dimethyl-1-pyrrolidinecarboxanilide) by excised leaves and cell suspension cultures of carrot and cotton

Major methanol-soluble metabolites of cisanilide (cis-2,5-dimethyl-1-pyrrolidinecarboxanilide) were isolated from excised, pulse-treated carrot and cotton leaves. They were identified as O-glucoside conjugates of primary aryl and alkyl oxidation products, 2,5-dimethyl-1-pyrrolidine-4-hydroxycarboxanilide and 2,5-dimethyl-3-hydroxy-1-pyrrolidinecarboxanilide. Comparative studies with carrot and cotton cell cultures showed similar initial pathways of cisanilide metabolism. Time-course studies with [¹⁴C-pyrrolidine]- and [¹⁴C-phenyl]cisanilide showed little, if any, cleavage of the herbicide molecule in either excised leaves or cell cultures. Quantitative differences in the metabolism of cisanilide by cell cultures and excised leaves included; a reduced capacity of cell cultures to form secondary glycoside conjugates and an increased ability of cell cultures to form methanol-insoluble residues.     

Synthetic pyrethroids: Toxicity and synergism on dietary exposure of Tribolium castaneum (Herbst) larvae

The potency of six dietary pyrethroids, as toxicants and inhibitors of weight gain in first- and fourth-instar Tribolium castaneum (Herbst) larvae, decreased in the order of cis-cypermethrin and deltamethrin > trans-cypermethrin and cis-permethrin > fenvalerate and trans-permethrin. Dosages that reduced larval weight also delayed pupation and emergence, probably due to their antifeeding activity. Three oxidase inhibitors (piperonyl butoxide, O, O-diethyl O-phenyl phosphorothioate, and O-isobutyl O-prop-2-ynyl phenylphosphonate), at a dietary concentration of 100 mg kg^?1, had little or no effect on the toxicity of trans-permethrin, but strongly synergised the toxicity of cis-cypermethrin by about 3-, 3- and 10-fold, respectively. Piperonyl butoxide also synergised the toxicity of cis-permethrin, trans-cypermethrin and deltamethrin, but not that of fenvalerate. On the other hand, an esterase inhibitor, profenofos, did not enhance the potency of any of the α-cyano-3-phenoxybenzyl pyrethroids. Oxidases appear to be more important than esterases in pyrethroid detoxification by T. castaneum larvae.     

The metabolism of the pyrethroid insecticide cypermethrin in rats; excreted metabolites

The metabolism of the pyrethroid insecticide cypermethrin has been studied in rats using three forms of ¹⁴C-labelling (benzyl-, cyclopropyl- and cyano-) and separate cis- and trans- isomers. The proportion of the dose absorbed from the intestines (50–70% at 2–3 mg kg^?1) is rapidly metabolised and eliminated. The major reaction is cleavage of the ester bond to afford the constituent cis- and trans- acids which are conjugated with glucuronic acid and eliminated in the urine. The 3-phenoxybenzyl portion of the molecule is probably released as the α-hydroxynitrile, which is converted via the aldehyde into 3-phenoxybenzoic acid. This compound is then largely hydroxylated and eliminated as a sulphate conjugate. The cyanide ion is metabolised via predictable routes, for instance, as thiocyanate. Cypermethrin is hydroxylated to some extent before hydrolysis. Most of this hydroxylation occurs at the methyl group trans to the cyclopropane carboxyl group, and at the 4-position of the phenoxy group. cis- Cypermethrin is slightly more stable than the trans-isomer.     

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 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.     

Degradation of juvenogens by termites and soil bacteria

Considering a potential application of selected biochemically activated insect hormonogen substances (juvenogens) against pest termite species, we aimed this study to describe the metabolism of these compounds by termites and soil bacteria and to evaluate the potential impact of their metabolites on the environment. Radiolabelled derivatives of the juvenogens cis- and trans-isomers of ethyl N-{2-[4-(2-butanoyloxycyclohexyl)methyl]phenoxy}ethyl carbamate were metabolized by the termite Reticulitermes flavipes and the bacteria Bacillus simplex and Bacillus sp., strain 05 (GenBank EU399813) giving rise to different numbers of metabolites. The trans-isomer of the juvenogen was metabolized by both Bacillus species into its parent synthetic structure, ethyl trans-N-{2-[4-(2-hydroxycyclohexyl)methyl]phenoxy}ethyl carbamate, while the cis-isomer was metabolized into further products. Both racemic juvenogens were metabolized bytermites, affording mainly the parent juvenoids. In terms of ecotoxicity, the trans-juvenogen shows a significantly lower toxicity than the cis-juvenogen. In contrast, the toxicity of the cis-juvenoid (main degradation product of cis-juvenogen) is higher than the toxicity of trans-juvenoid (main degradation product of trans- juvenogen). The precursors of the two juvenogens cis- and trans-2-(4-hydroxybenzyl)cyclohexanol were also tested but exhibited a low toxicity. The results demonstrate that bacteria can metabolize the juvenogen in liquid media culture and have implications for the development of a strategy for bioremediation of soil. Moreover, the products of the biodegradation exhibited low toxicity. Both juvenogens have a high juvenilizing effect, cause low mortality and are stable within a period of two weeks.     

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.     

Synergistic induction of wheat stem rust appressoria by chemical and topographical signals

The leaf alcohols cis -3-hexen-1-ol and trans -2-hexen-1-ol have been previously shown to induce the wheat stem rust (Puccinia graminis f. sp. tritici) to differentiate appressoria in a complex axenic culture medium. In this paper, the possible role of these chemicals in appressorium induction during infection has been analysed further. The inductive potential of ethylene and three cutin monomers were also tested because they have been found to induce appressoria in other fungi. Both hexenols were found to be inductive in aqueous solution in the absence of media constituents. 0.5–1 m trans -2-hexen-1-ol was the most inductive resulting in a maximum of 51% appressorium differentiation. trans -2-hexen-1-ol was also shown to be inductive in vapour form. In aqueous solution, trans -2-hexen-1-ol acted synergistically with topographical signals by increasing the rate of appressorium induction. Combining the two signals also increased the total number of appressoria differentiated (88%). The other chemicals tested were non-inductive although a biochemical domain rich in exposed cutin was localized around stomatal apertures of wheat leaves. The characteristic bipolar morphology of appressoria formed over stomata was found to be determined by topographical signals. Overall, our data support a role for both chemical signals (hexenols or their analogues) and topographical signals being involved in appressorium induction by wheat stem rust.     

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.     

The bromination of highly halogenated chrysanthemic acid analogues

(Z)-cis- and (Z)-trans-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclo-propanecarboxylic acids react with bromine under radical conditions predominantly to open the cyclopropane ring; the stereochemistry and reactions of the dibromides thus formed are described.     

Comparative testing of several juvenile hormone analogues in two species of locusts,Locusta migratoria migratorioides and Schistocerca gregaria

Effective treatment with juvenile hormone analogues (JHAs) of early penultimate or early last-instar locust hoppers induces a supernumerary ‘extra’ nymphal instar. These ‘extra’ nymphs, also termed ‘adultoids’, die in the course of, or shortly after, an ‘extra’ moult. Less effective treatment results in imperfect adults with crumpled twisted wings which presumably limit their flight and migratory abilities. Extremely effective treatment leads to death in the next moult. Comparing dose-response relations of (7S)-methoprene, fenoxycarb, pyriproxyfen and a new JHA, R70-1 (ethyl cis-N-{2-[4-(2-hydroxycyclohept-1-ylmethyl)phenoxy]ethyl}carbamate), we revealed that route of administration, instar of the recipient hopper, and species may alter over 1000-fold the ED₅₀ for the same JHA. Locusta migratoria migratorioides is much more susceptible to JHAs than Schistocerca gregaria. The lowest ED₅₀ found to induce adultoids and subsequent death in the ‘extra’ moult was 0·12 μg pyriproxyfen injected in olive oil to early penultimate instar hoppers of L. m. migratorioides (about 0·5 μg g^-1 fresh weight). R70-1 was more active than pyriproxyfen following the more practical topical application to early last-instar hoppers of L. m. migratorioides, 5·9 μg and 46 μg per hopper, respectively (about 10 μg g^-1 and 78 μg g^-1 fresh weight). The high susceptibility of last-instar L. m. migratorioides nymphs to topically applied R70-1 is promising from the practical standpoint. ©1997 SCI     

Distribution and depletion of [14C]resmethrin isomers administered orally to laying hens

The cis and trans isomers of the synthetic pyrethroid resmethrin, labelled with radiocarbon in either the alcohol or acid moiety, were individually administered orally to White Leghorn laying hens at a dosage of 10 mg kg^?1. With each isomer and label position, greater than 90% of the radiocarbon was eliminated in the excreta within 24 h after the treatment. Radiocarbon residues in the egg white and yolk fractions were low, with peak levels observed 1 and 4-5 days after treatment in white and yolk, respectively. In birds sacrificed 12 h after treatment, radiocarbon residues in tissues were low; the highest levels were found in the liver and kidney.