Quantitative structure–activity studies of optically active 2-methoxy-1,3,2-oxazaphospholidine 2-sulfides against Musca domestica L

The quantitative relationship between the structure of optically active 4-substituted 2-methoxy-1,3,2-oxazaphospholidine 2-sulfides (4-RMOS) and their insecticidal activity on the house fly, Musca domestica L., was analysed using reported physicochemical parameters and regression analysis. The configuration at the C₄ atom was more important for insecticidal activity than that at the phosphorus atom, since the coefficient of the dummy parameter for the C₄- configuration was larger than that for the configuration of the phosphorus atom: (S)c(R)p diastereoisomers showed the highest insecticidal activity, and the activity decreased in the order of (S)c(R)p > (S)c(S)p > (R)c(R)p > (R)c(S)p. The electronic nature of the substituent at the C₄ position was the most important, followed by the steric and hydrophobic effects: the more electron-donating, the less bulky and the more hydrophobic the 4-substituent, the higher the insecticidal activity. Thus the highest activity was obtained for the isopropyl derivatives, and the activity decreased in the order of isopropyl > isobutyl > ethyl > sec-butyl > benzyl > phenyl > methyl > tert-butyl.     

Quantitative Structure–Activity Relationships of DDT-Type Compounds in a Sodium Tail-Current in Crayfish Giant Axons

Effects of DDT-type compounds including 1,1-bis(para-substituted phenyl)-2,2-dichlorocyclopropanes (DCC-series compounds) on sodium currents in crayfish giant axons were measured under voltage-clamp conditions. Variations in the activity to prolong the tail-current that was observed upon step repolarization of the membrane were quantitatively analysed by use of physicochemical parameters of aromatic substituents and regression analysis. Introduction of lengthy and narrow substituents was favourable to the activity. Variations in the activity were parabolically related to the hydrophobicity, optimum value being around that of H. DDT- and prolan-series compounds were 2–3 times more active than DCC-series compounds when other structural factors were the same. Insecticidal activity of the compounds was linearly correlated with the tail-current activity when the hydrophobic factor was separately considered. The insecticidal activity of DDT-series compounds was 2·5 times higher than that of others when the other factors were the same. © 1997 SCI.     

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.     

Synthesis and insecticidal activity of novel 1,3,4-oxadiazolin-5-one and pyrazolin-5-one derivatives

A series of novel 2-(2,4,6-trisubstituted phenyl)-1,3,4-oxadiazolin-5-one derivatives and 3-(2,4,6-trichlorophenyl)pyrazolin-5-one derivatives were synthesized and evaluated for insecticidal activity. It was found that a moderately bulky alkyl group, such as a tert-butyl group, on the heterocyclic ring, and a trifluoromethyl group on the benzene ring were optimal substituents on the molecule. The oxygen atom in the oxadiazoline ring was essential for insecticidal activity. Of the compounds assayed, 4-tert-butyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-5-one gave the highest activity against Nephtotettix cincticeps, with an LC₅₀ value of 0.51 mg litre⁻¹. © 1999 Society of Chemical Industry     

Insecticidal properties of benzofuran-2-carboxylic acid derivatives

A series of amides and esters of substituted benzo[b]furan-2-carboxylic acids have been synthesised, and their activity against adult sweet potato weevils, Cylas formicarius elegantulus (Summer) studied. The topical insecticidal potency of these compounds was compared in acetone solution and in a mixture of piperonyl butoxide (PB) and acetone (0·05+99·95 by volume). The compounds were much more active when administered in the acetone/PB mixture, and exhibited 48-h LD₅₀ values ranging from 1·7 to 26·6 μg per insect. The most active compound, 2-(3,5-dimethylpyrazol-1-ylcarbonyl)-6-methoxy-3-methylbenzofuran, was equiactive with technical grade dimethoate (in acetone/PB) on a weight basis. © 1998 SCI     

Quantitative structure-activity studies of pyrethroids: 12. Physicochemical substituent effects of meta-phenoxybenzyl α,α-disubstituted acetates on insecticidal activity

The insecticidal activity of a series of m-phenobenzyl esters of iso-valeric and tert-butylacetic acids, the α-position of which was substituted with one of alkyl, alkoxyalkyl, alkoxy, benzyl, phenyl, phenoxy, and anilino groups, was measured by injection into American cockroaches under synergistic conditions to suppress possible oxidative and hydrolytic metabolism. Their neuroexcitatory activity on nerve preparations excised from the cockroaches was measured by an extracellular recording technique. The activities of the analogous esters of cyclopropanecarboxylic acids with a substituted vinyl side chain were also measured. The insecticidal activity was quantitatively analyzed with physicochemical parameters for the α-substituent or its counterpart of the acid moiety. Variations in the activity were related parabolically to both the hydrophobicity and the length of the substituent. The activity of compounds, the α-substituent of which is either a substituted phenyl or a phenoxy group, was about 10 times that of compounds with “physicochemically equipvalent” aliphatic substituents. α-Substitution with ring-substituted anilino groups, but not with N-methyl groups, enhanced the activity about 25 times, but the vinylcyclopropane structure raised the activity to about 60 times that of physicochemically equivalent aliphatic noncyclopropane substituents. Variations in the insecticidal activity were closely related to those in the neuroexcitatory activity when hydrophobic and steric factors were separated. The steric factor in addition to the hydrophobicity seemed to be important in the transport process.     

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.     

Synthesis and structure–activity relationships of carbohydrazides and 1,3,4‐oxadiazole derivatives bearing an imidazolidine moiety against the yellow fever and dengue vector,Aedes aegypti

BACKGROUND

1,3,4‐Oxadiazole and imidazolidine rings are important heterocyclic compounds exhibiting a variety of biological activities. In this study, novel compounds with oxadiazole and imidazolidine rings were synthesized from 3‐(methylsulfonyl)‐2‐oxoimidazolidine‐1‐carbonyl chloride and screened for insecticidal activities. The proposed structures of the 17 synthesized compounds were confirmed using elemental analysis, infrared (IR), proton nuclear magnetic resonance (¹H‐NMR), and mass spectroscopy.

RESULTS

None of the compounds showed larvicidal activity at the tested concentrations against first‐instar Aedes aegypti larvae. However, nine compounds exhibited promising adulticidal activity, with mortality rates of ≥80% at 5 µg per mosquito. Further dose–response bioassays were undertaken to determine median lethal dose (LD₅₀) values. Compounds 1 , 2b , 2c , 2d , 2 g , 3b , 3c , 3 g, and 3 h were effective, with typical LD₅₀ values of about 5 ? 10 µg per mosquito against female Ae. aegypti. Compounds 2c (bearing a nitro group on the aromatic ring; LD₅₀ = 2.80 ± 0.54 µg per mosquito) and 3 h ( double halogen groups at 2,4 position on the phenyl ring; LD₅₀ = 2.80 ± 0.54 µg per mosquito) were the most promising compounds.

CONCLUSION

Preliminary mode of action studies failed to show consistent evidence of either neurotoxic or mitochondria‐directed effects. Further chemical synthesis within this series may lead to the development of new effective insecticides. © 2017 Society of Chemical Industry

     

The pyrethrins and related compounds. Part XXXVII. synthesis and insecticidal properties of new 1-aryl-1-(3-arylpropyl and -propenyl)cyclopropanes (non-ester pyrethroids)

New routes to the title compounds, involving improved conditions for the cyclopropanation, and a new method of constructing the central three-carbon unit (based on the coupling of a Grignard reagent with an allylic acetate) give access to products for which the previously reported route was not satisfactory. For the new route, a synthesis of 5-bromo-2-fluoro-diphenyl ether was developed. Previously deduced relationships between structure and insecticidal activity apply for the new compounds: alkenes are generally more active than corresponding alkanes; substitution at the 3- or 4-position (but not the 2-) of the 1-aryl group can enhance activity. In addition, some fluorine-containing substituents lead to high activity.     

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.     

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     

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.     

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     

Bicyclophosphorothionate antagonists exhibiting selectivity for housefly GABA receptors

2,6,7-Trioxa-1-phosphabicyclo[2.2.2]octane 1-sulfides (bicyclophosphorothionates) with various C_1–4 alkyl groups at the 3- and 4-positions were synthesized and tested for their ability to compete with [³H]4′-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of γ-aminobutyric acid (GABA) receptors, for specific binding to rat-brain and housefly-head membranes, and for their insecticidal activity against houseflies. Among the 3,4-substituted analogues, 20 compounds were selectively active for housefly GABA receptors versus rat GABA receptors. The 3-alkyl groups of C₃ length and the 4-alkyl groups of C₄ length were tolerated in housefly receptors, whereas such bulky substituents were deleterious in rat receptors. The 4-isobutyl-3-isopropyl analogue was the most potent in housefly receptors (IC₅₀ = 45.2 nM ), and tert-butylbicyclophosphorothionate (TBPS), with the 4-tert-butyl group and no 3-substituent, was the most potent in rat receptors (IC₅₀ = 62.2 nM ). Their receptor selectivities (rat IC₅₀/housefly IC₅₀) were 52 and 0.038, respectively. The insecticidal activity (LD₅₀) of 20 active analogues was well correlated with their potency (IC₅₀) in inhibiting [³H]EBOB binding to housefly-head membranes (r = 0.93). The results obtained in the present study indicate that the introduction of appropriate alkyl groups into the 3- and 4-positions of bicyclophosphorothionate leads to non-competitive antagonists with increased affinity and selectivity for housefly ionotropic GABA receptors versus rat GABA_A receptors. © 1999 Society of Chemical Industry     

Binding activity of substituted benzyl derivatives of chloronicotinyl insecticides to housefly‐head membranes,and its relationship to insecticidal activity against the housefly Musca domestica

Variously substituted benzyl derivatives of chloronicotinyl insecticides were synthesized with a wide range of substituents including halogens, NO₂, CN, CF₃ and small alkyl and alkoxy groups at the ortho, meta and para positions, as well as multiple‐substituted benzyl analogues. Their binding activity to the α‐bungarotoxin binding site in housefly (Musca domestica) head membrane preparations was measured. Among the compounds tested, the activity of the meta‐CN derivative was the highest, being 20–100 times higher than those of imidacloprid, acetamiprid and nitenpyram. The synergized insecticidal activity against houseflies was also measured for selected compounds with the metabolic inhibitor, NIA16388 (propargyl propyl phenylphosphonate). For the nitromethylene analogues, including both benzyl and pyridylmethyl analogues, higher binding activity usually resulted in higher insecticidal activity. © 2000 Society of Chemical Industry     

Transformation rates of ortho-substituted thiophene and benzene carboxylic esters: Application to thifensulfuron-methyl and metsulfuron-methyl herbicides

The rate constants for soil degradation and alkaline hydrolysis of two herbicides, metsulfuron-methyl and thifensulfuron-methyl, have been determined. In order to explain the difference in behaviour of the two compounds, the chemical and enzymatic hydrolysis of some ortho-substituted methyl benzoates and methyl 3-substituted thiophene-2-carboxylates were studied. The data are consistent with a difference in polar and steric effects of the substituents in benzene and thiophene derivatives.     

Synthesis and insecticidal and acaricidal properties of some 5-methoxy-1-methyl-6-oxo-1H-pyridazin-4-yl phosphorus esters. III

A series of new 5-methoxy-1-methyl-6-oxo-1H-pyridazin-4-yl phosphorus esters, which was prepared by phosphoroylation of 5-methoxy-1-methyl-6-oxo-1H-pyri-dazin-4-ol, is described. Many of the compounds showed high insecticidal and acaricidal activity.     

Quantitative structure-activity relationships of herbicidal N′-substituted phenyl-N-methoxy-N-methylureas

Relationships between three types of herbicidal activity of N′-substituted phenyl-N-methoxy-N-methylureas and substitution at the benzene ring were analyzed by the Hansch-Fujita method. First, the Hill inhibitory activity was correlated with electronic (σ) as well as hydrophobic (π) substituent constants. The existence of an optimum value of hydrophobicity for substituents was suggested to reach the target site of action. Second, bliaching activity observed for the 3-substituted but not for 4-substituted compounds was correlated with π, σ, and steric substituent constant, E_s. Third, the postemergent herbicidal activity was shown to correlate linearly with the Hill inhibitory activity, pI₅₀, and hydrophobic parameter, π.     

Acute and delayed neurotoxicity of leptophos analogs

Nineteen O-halogenated-phenyl O-methyl phenylphosphonothionates were evaluated for acute toxicity (LD₅₀) to the female house fly Musca domestica L. and to the male Swiss white mouse, and for delayed neurotoxicity to the White Leghorn hen. The electron-withdrawing power of the phenyl substituents (Σσ^? values) correlate with the LD₅₀ values to house fly and mouse, with departures from linearity attributable to the steric hindrance of di-ortho-Cl substitution and by variations in the accessibility of the anionic site of acetylcholinesterase in the two species. The relationship with delayed neurotoxicity is less predictable although it clearly depends on suitable electron-withdrawing capacity. Delayed neurotoxicity also relates to a high degree of lipophilicity and prolonged residence time of the inhibitor in the nerve axon.     

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.