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.     

Synergism by Propynyl Aryl Ethers in Permethrin-Resistant Tobacco Budworm Larvae,Heliothis virescens

Synergists were used to diagnose possible mechanisms of permethrin resistance in permethrin-selected strains of the tobacco budworm, Heliothis virescens (F.). In addition to permethrin, these strains of the tobacco budworm were resistant to α-cyano-pyrethroid insecticides, organophosphorus insecticides and DDT. The monooxygenase-inhibiting prop-2-ynyl aryl ethers were the only effective synergists of permethrin among 16 candidates tested. The most effective synergist was 1,2,4-trichloro-3-(2-propynyloxy)benzene. Piperonyl butoxide, a common monooxygenase-inhibiting synergist in other species and tobacco budworm strains, was inactive. These results suggested the presence and contribution of an unusual monooxygenase in the enzymatic detoxication of permethrin. DDT cross-resistance, which was not synergized, and broad pyrethroid cross-resistance supported previous evidence for target site insensitivity as a second pyrethroid-resistance mechanism in these strains. The actions of S,S,S-tributyl phosphorotrithioate (TBPT) and triphenyl phosphate (TPP) suggested that hydrolytic detoxication, important in methyl parathion-resistance tobacco budworm strains, had little or no role in conferring pyrethroid resistance in these strains.     

Inhibitors of juvenile hormone biosynthesis in corpora allata of the cockroach Periplaneta americana (L.) in vitro

The spontaneous biosynthesis of methyl (2E,6E)-(10R)-10,11-epoxy-3,7,11-trimethyldodeca-2,6-dienoate (juvenile hormone III; JH III) in excised corpora allata of Periplaneta americana was inhibited by a number of synthetic prop-2-ynyl ethers and 1,3-benzodioxole derivatives. One structurally diverse group of compounds inhibited only the final biosynthetic enzyme methyl farnesoate epoxidase (EC.1.14.14.–) at low to moderate concentrations, but at higher concentrations, also inhibited methyl farnesoate (MF) formation, causing an accumulation of MF in the concentration range 10 to 100 μM. For a second, more limited, group of compounds, there was close congruence between the inhibition of JH III biosynthesis and that of total ester (MF plus JH III) biosynthesis over their effective inhibitory concentration ranges. In contrast to the first group, there was no accumulation of MF and these compounds evidently inhibited JH III biosynthesis, at the level of either farnesoic acid esterification by O-methyl transferase (EC.2.1.1.–), or at an earlier step in the biosynthetic pathway that remains to be elucidated.     

Insecticidal activity of the pyrethrins and related compounds. VII. Insecticidal dihalovinyl analogues of cis and trans chrysanthemates

Eighteen esters of resolved cis- and trans-3-(2,2-difluoro, -dichloro or -dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acids with 5-benzyl-3-furylmethyl, 3-phenoxybenzyl and α-cyano-3-phenoxybenzyl alcohols were prepared and evaluated for insecticidal activity against Musca domestica L. and Phaedon cochleariae Fab. Chlorine and bromine substituted esters are more active, in general, than those with fluorine, and in the most active esters, the cis isomer is more effective than the trans.     

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.     

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.     

The pyrethrins and related compounds. XIX Geometrical and optical isomers of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid and insecticidal esters with 5-benzyi-3-furylmethyi and 3-phenoxybenzyl alcohols

Esters of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylic acid with appropriate alcohols are more active insecticides than the corresponding 3-isobutenyl compounds (chrysanthemates). (±)-Cis and (±)-trans forms of the dichloro acid are obtained by fractional crystallisation of the mixed acids or by hydrolysis of the ethyl esters separated by fractional distillation. The (±)-cis and (±)-trans acids are resolved into their (+)- and (-)-forms with α-methyl-benzylamine and threo-l-p-nitrophenyl-2-N,N-dimethyiamino-propane-1,3-diol respectively. As for the corresponding chrysanthemates, the (+)-cis and (+)-trans acids give esters more active as insecticides than their enantiomers.     

The action of pyrethroids in the insect central nervous system. I. Features of molecular structure associated with toxicity to cockroaches and to their giant fibre axons

To investigate relationships between the molecular structure of pyrethroids and their mode of action, toxicities to adult male Periplaneta americana by topical application and injection were compared with toxicities to their giant fibre nerve axons. From the tests against intact insects it was concluded that: (i) although ED₅₀S ranged from 0.04 to 65 μg/insect, each compound was equally toxic, with one exception, when administered by either route; (ii) esters of (1 R)-cis- were more toxic than esters of the corresponding (1 R)-trans-3-substituted-2, 2-dimethylcyclopropanecarboxylic acids; (iii) α-cyano-3-phenoxybenzyl esters were more toxic than the corresponding 3-phenoxybenzyl esters; (iv) changes in the alcoholic component of some compounds (particularly trans-isomers of esters of 5-benzyl-3-furylmethanol and esters of α-cyano-3-phenoxybenzyl alcohol) affected a recovery phase in their ED₅₀/time curves more than changes in the acid component; (v) the amount of recovery was positively correlated with molecular polarity. The concentration required to decrease the amplitude of the action potential of giant fibres by 30% in 1 h ranged from 0.26 μM for the most active compound to 100 μM for the least active. There was no clear relationship between neurotoxicity and toxicity to whole insects and little association between neurotoxicity and features of molecular structure. Neurotoxicity was, however, positively correlated with polarity. Giant fibre axons seem unlikely to be critical sites of action of pyrethroids.     

The pyrethrins and related compounds. Part XXXVIII—optimisation of insecticidal activity in 3-[(alkoxyimino)methyl]-4-fluorobenzyl esters

Optimisation of activity in 3-[(alkoxyimino)methylbenzyl] esters has been investigated by introducing an α-cyano group and a fluorine atom in position 4 of the benzylic moiety in conjunction with varying the length and nature of the side chain. Of the five side-chain variations investigated, the 3-methoxyiminomethyl was more effective than others. Introduction of fluorine in position 4 of the benzylic moiety generally increased activity, particularly against mustard beetles, as in previous instances. Surprisingly, the effect on insecticidal activity of introducing an α-CN group ranged from positive to negative depending upon the nature of the alkoxyimino substituent, an effect not observed previously. The most effective esters were derived from α-cyano-4-fluoro-3-[(methoxyimino)methyl]benzyl alcohol, which was synthesised from 2-{4-fluoro-3-[(hydroxyimino)methyl]phenyl}-1,3-dioxolane.     

Insecticidal activity of the pyrethrins and related compounds. Part XII: α-substituted-3-phenoxybenzyl esters

Seventy-three α-substituted 3-phenoxybenzyl esters were synthesised, mostly using one of two general routes, based on the Grignard and related reactions. Esters with simpler (smaller and more polar) α-substituents were generally more insecticidally active; correlations based on substituent volume and substituent polarity parameters were about equally significant.     

Structure—activity relationships in pyrethroid esters derived from substituted 2-phenoxy-3-methylbutanoic acids

Non-cyclopropane pyrethroid esters of different substituted 2-phenoxy-3-methylbutanoic acids have been synthesised using the three alcohols—3-phenoxybenzyl alcohol, α-cyano-3-phenoxybenzyl alcohol and 3, 4-methylene-dioxybenzyl alcohol. Among the 35 esters synthesised and tested against Culex quinquefasciatus Say, the Bancroftian filariasis vector, for both larvicidal and adulticidal activities, α-cyano-3-phenoxybenzyl 2-(4-fluorophenoxy)-3-methylbu-tanoate, with an LC₅₀ value of 2.5 × 10^?3 mg litre^?1 for larvicidal activity, and α-cyano-3-phenoxybenzyl-2-(4-chlorophenoxy)-3-methylbutanoate, with an LD₅₀ value of 30 times; 10^?4 ug insect^?1 for adulticidal activity, were found to be as effective as fenvalerate, a well-known non-cyclopropane pyrethroid ester. Structure-activity studies showed that the insecticidal activity is dependent on the nature and position of the substituent in the phenyl ring of the acid moiety and also on the type of alcohol moiety.     

Genetic and biochemical studies of resistance to permethrin in a pyrethroid-resistant strain of the housefly (Musca domestica L.)

One or more weak factors of resistance on autosome 2, and barely detectable resistance on autosome 3, confer moderate resistance to several pyrethroids (5–13-fold) in the field-collected Ipswich strain of houseflies. In these flies, which unlike other pyrethroid-resistant strains lack kdr or super-kdr, pyrethroid resistance probably developed in response to prolonged treatment of buildings for animals with pyrethrins synergised with piperonyl butoxide. Substrains, isolated genetically from Ipswich flies and with resistance only on autosome 2, degraded permethrin more rapidly than susceptible flies and produced larger amounts of very polar metabolites. In this, they differed from flies with kdr or super-kdr which resembled susceptible flies in their metabolism of permethrin. NIA 16388 (propyl prop-2-ynyl phenylphosphonate) was a better synergist and reduced the metabolism of permethrin more than piperonyl butoxide in both the susceptible and resistant insects. The slight increase in synergism and minimal decrease in metabolism when piperonyl butoxide was applied with NIA 16388 indicated that the latter also inhibited detoxication that was sensitive to piperonyl butoxide.     

The pyrethrins and related compounds. Part XXX: Esters from acids with mono-halovinyl side chains

Esters of 3-phenoxybenzyl alcohol and its α-cyano derivative with 2,2-dimethylcyclopropanecarboxylic acids bearing (E)- or (Z)-3-monohalovinyl side chains (haloiodo, bromo, chloro or fluoro) were synthesised and had moderate to high insecticidal activities, but these were generally lower than those of established pyrethroids with the corresponding 3-(dihalovinyl) side chains. Compounds with 3-(2-chloroprop-1-enyl) side chains were intermediate in potency between the related chrysanthemates and 3-(dichlorovinyl) esters.     

The pyrethrins and related compounds; Part XXIII:Kinetic control in the formation of pyrethroidal estersb

The unequal amounts of the two diastereomers of (RS)-1-(3-phenoxyphenyl)ethyl (RS)-2-(4-chlorophenyl)-3-methylbutyrate, obtained from equimolar proportions of the alcohol and acyl chloride under normal conditions, imply stereoselectivity in the reaction. The extent to which this depends on the nature of the α-substituent for arange of 3-phenoxybenzyl esters, on the nature of the acid, and on the method of esterification is investigated. Selectivity arises from kinetic, rather than thermodynamic control.     

Structure and insecticidal activities of pyrethroids available through new methods of synthesis

Starting from derivatives of cyclobutanone the synthesis is described of α-cyano-3-phenoxybenzyl esters of 2,2-dimethylcyclopropanecarboxylic acid, substituted in the 3-position of the cyclopropane ring by an alkoxy, alkylthio, phenoxy or phenylthio group. The insecticidal activities of these synthetic pyrethroids towards adult Musca domestica, and larvae of Aedes aegypti, Spodoptera littoralis and Heliothis virescens are reported and compared with known pyrethroids.     

Antifeedant and toxicity effects of thiophenes from four Echinops species against the Formosan subterranean termite, Coptotermes formosanus

Over 220 crude extracts from repositories generated from plants native to Greece and Kazakhstan were evaluated for termiticidal activity against the Formosan subterranean termite, Coptotermes formosanus Shiraki (Isoptera: Rhinotermitidae). Emerging from this screening effort were bioactive extracts from two Greek species (Echinops ritro L. and Echinops spinosissimus Turra subsp. spinosissimus) and extracts from two Kazakhstan species (Echinops albicaulis Kar. & Kir. and Echinops transiliensis Golosh.). Fractionation and isolation of constituents from the most active extracts from each of the four species has been completed, resulting in the isolation of eight thiophenes possessing varying degrees of termiticidal activity. 2,2':5',2"-Terthiophene and 5'-(3-buten-1-ynyl)-2,2'-bithiophene demonstrated 100% mortality against C. formosanus within 9 days at 1 and 2 wt% concentrations respectively. In addition, all but two of the eight compounds tested were significantly different from the solvent controls in the filter paper consumption bioassay.     

2-arylalkanoates,a new group of synthetic pyrethroid esters not containing cyclopropanecarboxylates

Although structure modifications of natural pyrethrin constituents have disclosed a variety of potent synthetic analogues, all known examples are cyclopropanecarboxylate esters, a grouping that appeared to be essential for insecticidal activity. Some new substituted 2-phenylalkanoates, whose biological activities are of a similar nature and potency to those of conventional pyrethroids, are now reported. 5-Benzyl-3-furylmethyl and 3-phenoxybenzyl 3-methyl-2-phenylbutyrates and their analogues are potent insecticides. Activity is increased on the introduction of appropriate groups into the 3 and/or 4-positions of the aryl ring and the (S)-2-phenylalkanoates are far more active than their (R)-enantiomorphs. Structure/activity relationships are compared with those for conventional pyrethroids. Some of the new series compare favourably with typical insecticides in tests against Musca domestica, Spodoptera litura and Plutella xylostella.     

The pyrethrins and related compounds. Part XXIX: Haloallylbenzyl esters

Synthesis and bioassay of a series of esters based on pyrethroidal acids established that the activity of halosubstituted allylbenzyl esters depends on the position and stereochemistry of substitution in the allyl side-chain, on the substitution pattern on benzyl, on the esterifying acid, and, to a lesser extent, on the nature of the halogen substituent itself. The most powerful combination of the first four parameters for activity against houseflies is in (Z)-3-haloallylbenzyl esters of the (1R)-cis 3-(2,2-dibromovinyl) acid. Other combinations have moderate to low activity. Some aspects of the variation conform to previously recognised patterns, others define more precisely the requirements for the side-chain to confer activity. The pattern of response of activity to cyano-substitution at the α-position, noted earlier, persists in the current compounds, and is here analysed quantitatively.     

Insecticidal activity of the pyrethrins and related compounds. Part XIIIa: Comparison of the effects of a-substituents in different esters

The insecticidal activities of esters from a series of alcohols with four different groups (H, -CH₃, -C?CH and -C?N) in the α-position, and containing different A-rings or bridging groups, were evaluated. The results show a complex interaction between these two parts of the molecule; the strongest enhancement of activity by some α-substituents was found in 3-phenoxybenzyl esters, while other systems responded weakly or even negatively to the substitution.     

The inhibition of insect juvenile hormone esterase by trifluoromethylketones: Steric parameters at the active site

A rationally designed structure-activity relationship study has been accomplished using trifluoromethylketone inhibitors of insect juvenile hormone esterase from the cabbage looper, Trichoplusia ni (Hubner) (Lepidoptera: Noctuidae). Several α- and α′-substituted derivatives of 3-octylthio-1,1,1-trifluoropropan-2-one have been prepared and assayed for inhibitory potency against juvenile hormone esterase. The results indicate that the sulfur/protein interaction does not occur in a sterically constrained environment. Substitution adjacent to sulfur did not dramatically effect activity. However, substitution adjacent to the carbonyl of the trifluoromethylketone moiety reduced inhibitory potency substantially, indicating that the active site region of juvenile hormone esterase which interacts with the carbonyl is restricted to rather small substrates. A small hydrophobic pocket near the active site has been identified and can serve to increase inhibitory potency by secondary binding of appropriate substituents. The present study has resulted in the preparation of two more effective in vitro inhibitors of juvenile hormone esterase than those previously reported. Evidence that there are two naturally occurring forms of juvenile hormone esterase has also been provided.