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.     

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 study of insecticidal 2-methoxy-5-(substituted-phenyl)-1, 3, 2-oxazaphospholidine 2-sulfides against Musca domestica L. by topical application

The quantitative relationship between the structure of 2-methoxy-5-(substituted-phenyl)-1, 3, 2-oxazaphospholidine 2-sulfides (5-PMOS) and their insecticidal activity against the house fly. Musca domestica L., was analyzed using reported physicochemical parameters and regression analysis. The electronic nature of the substituent on the phenyl group of 5-PMOS has the most significant effect on the activity, followed by hydrophobic and steric effects; the optimum value of Σρ is zero and the more hydrophobic the substituents on the phenyl group, the higher the insecticidal activity. The plots of observed pLD₅₀, values against calculated pLD₅₀ values for compounds having substituents in the ortho-position deviated downwards from those of compounds having substituents at the meta and/or para positions. This ortho-effect, which reduces the insecticidal activity of compounds having substituents at the ortho-position, was expressed by a dummy parameter D, which has the value 2 for di-ortho-substituted derivatives, 1 for mono-ortho-substituted derivatives and zero for others. Thus, the highest activity was obtained for 2-methoxy-5-phenyl-1, 3, 2-oxazaphospholidine 2-sulfide, and the activity was decreased by the introduction of any substituents on the phenyl group.     

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.     

Quantitative structure-activity studies of benzoylphenylurea larvicides: I. Effect of substituents at aniline moiety against Chilo suppressalis walker

The larvicidal activity of a series of N-2,6-difluoro- and N-2,6-dichlorobenzoyl-N′-(4-substituted phenyl)ureas against nondiapause larvae of the rice stem borer, Chilo suppressalis Walker, was measured by topical application and oral administration methods under conditions with and without piperonyl butoxide as an inhibitor of oxidative metabolism. The effects of substituents at the anilide moiety on the larvicidal activity were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results indicate that the oxidative metabolism in the larval body which is favored by electron-donating substituents is significant in determining the activity. The activity, when the metabolic factor is eliminated, is enhanced by electron-with-drawing and hydrophobic substituents and lowered by bulky groups. The inhibitory activity against new cuticle formation of the same series of compounds was also measured using cultured integument of the rice stem borer diapause larva. The comparison of the quantitative analyses between larvicidal and integument-level activities shows that inhibition of cuticular development is the most important factor governing larvicidal activity.     

Quantitative structure-activity studies of benzoylphenylurea larvicides: II. Effect of benzyloxy substituents at aniline moiety against Chilo suppressalis Walker

The larvicidal activity of a series of N-2,6-difluorobenzoyl-N′-[4-(substituted benzyloxy)-phenyl]-ureas against nondiapause larvae of the rice stem borer, Chilo suppressalis Walker, was measured by a topical application method under conditions in which oxidative metabolism was inhibited by piperonyl butoxide. The effects of the substituted-benzyloxy moiety on variations in the activity were analyzed quantitatively using physicochemical substituent parameters and regression analysis. Results were compared with those found previously for N-2,6-difluorobenzoyl-N′-(4-substituted phenyl)-ureas, indicating that the electron-withdrawing property of the anilide substituents participates in determining the activity through the inductive effect. The hydrophobicity of the total anilide substituents favors activity, whereas the steric dimension in terms of the width lowers it. Although inhibition of new cuticle formation on cultured integument of diapausing larva could not be determined accurately for most of the compounds because of their limited solubility in the assay medium, inhibitory activity seemed related to larvicidal activity, as was the case for previously investigated simpler congeners.     

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 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.     

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.     

Quantitative structure–fungicidal activity relationships of N-(4-difluoromethoxybenzyl)­pyrimidin-4-amines against wheat and barley fungi

A set of N-(4-difluoromethoxybenzyl)pyrimidinamines with various substituents at the 4- and 5-positions of the pyrimidine ring and at the benzyl position were prepared, and their fungicidal activities against wheat brown rust, Puccinia recondita, and barley powdery mildew, Erisiphe graminis, were measured. Variations in each of these activities were quantitatively analysed by the use of physicochemical substituent parameters and a regression analysis. Each of these activities was parabolically correlated with the steric bulkiness of the pyrimidine substituents and with the bulkiness or the hydrophobicity of the benzylic substituents. © 1999 Society of Chemical Industry     

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 antifungal N-phenylsuccinimides and N-phenyl-1,2-dimethylcyclopropanedicarboximides

The antifungal activity of 61 N-phenylsuccinimides and 16 N-phenyl-1,2-dimethylcyclopropanedicarboximides having various benzene ring substituents was determined against Botrytis cinerea by the agar medium dilution method. The structure-activity relationships were analyzed using such physicochemical substituent parameters as hydrophobic π, electronic σ⁰, steric E₈, and HB (hydrogen bonding) values with the multiple regression technique. The π values were derived from log P (octanol-water partition coefficient) values for the N-monosubstituted-phenylsuccinimide system. The hydrophobic effect is significant only for m-substitutents. The stronger the electron withdrawal and the smaller the steric dimensions of the ring substituents, the greater is the activity. When substituents are hydrogen bond acceptors, the effect is to lower the activity. These features are almost identical between two series of compounds.     

Quantitative structure-activity relationships of the fungicidal methyl N-phenylcarbamates

For 69 methyl N-phenylcarbamates having various benzene ring substituents, the fungicidal activity was determined against Botrytis cinerea resistant to benzimidazole fungicides by the agar medium dilution method. The structure-activity relationships were analyzed quantitatively using such physicochemical substituent parameters as hydrophobic π, steric B₅, and HB (hydrogen bonding) with the Hansch-Fujita method (C. Hansch and T. Fujita, J. Amer. Chem. Soc.86, 1616 1964). The hydrophobicity of substituents was favorable to the acitivity. The effect was position-specific, the importance being in the order of ortho meta > para. The activity was related parabolically to the maximum width of one of the m-substituents having the larger dimension. The hydrogen acceptability of p-substituents enhanced the activity. The preventive activity of compounds against gray mold of cucumber caused by the resistant B. cinerea, which was determined by the foliar application in pot tests, was dependent on the magnitude of the fungicidal activity and hydrophobicity of the compounds as analyzed by the adaptive least-squares method.     

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.     

Quantitative structure–activity studies of insect growth regulators: XVI. Substituent effects of dibenzoylhydrazines on the insecticidal activity to Colorado potato beetle Leptinotarsa decemlineata

Insecticidal activity against the Colorado potato beetle, Leptinotarsa decemlineata, was measured for a series of substituted N-tert-butyl-dibenzoylhydrazines, in which one of the benzoyl moieties closer to the tert-butyl group was fixed as being 2-chloro-substitued and the other variously substituted singly or doubly. The effects of substituents on the activity were quantitatively analysed using the classical quantitative structure–activity relationship (QSAR) procedure. The activity against the Colorado potato beetle increases with the molecular hydrophobicity. In addition, various types of steric effect are at work, depending upon the positions. Hydrogen-bonding acceptor substituents at the para position enhance the activity. There seem to be threshold (or optimum) values, albeit position-dependent, in the molecular hydrophobicity, above which the activity starts to decrease. This biphasic contribution of the molecular hydrophobicity to activity against coleopterous larvae is the most conspicuous difference in substituent effects from those found for similar compounds against lepidopterous pest insects, and may be the basis of the variations in the activity spectrum for certain compounds in this series. The introduction of bulkier substituents into the meta- and para-positions of the benzene ring, apart from the tert-butyl group, is unfavorable to activity. LD₅₀ values against Colorado potato beetle larvae of methoxyfenozide (RH-2485) and tebufenozide (RH-5992) were in the order of 10⁻⁷ mol per insect, whereas those of RH-5849, and halofenozide (RH-0345) were very low, 10⁻⁹–10⁻¹⁰ mol per insect being selective to the coleopterous larvae. © 1999 Society of Chemical Industry     

Structural Effects of N-Arylcarbamoylpyrazolines on Calcium Uptake in Rat Brain Synaptosomes

N-Arylcarbamoylpyrazolines with various substituents at the para position of the carbamoyl benzene ring inhibited ATP-dependent Ca²⁺-uptake in synaptosomes prepared from the rat brain. The activity of these compounds was evaluated as log(1/I₅₀), the reciprocal logarithm of half inhibitory concentration, I₅₀ (m ), from the concentration–response curve for the inhibition of Ca²⁺-uptake. Among the compounds tested, methyl 3-(4-chlorophenyl)-4-methyl-1-[N-(4-trifluoromethylphenyl)carbamoyl]-2-pyrazoline-4-carboxylate was the most potent, the I₅₀ value of which as 9·12×10⁻⁷ m . Variations in the activity in terms of log(1/I₅₀) were quantitatively analysed using a substituent parameter, showing that the higher the electron-withdrawing effect of the substituent, the higher was the activity. The substituent effects were similar to those on insecticidal activity against the Americal cockroach. The higher the inhibitory activity against Ca²⁺ uptake, the higher seemed to be the insecticidal activity. Methyl(4S) - 3 - (4 - chlorophenyl) - 4 - methyl - 1 - [N - (4 - chlorophenyl)carbamoyl] - 2 - pyrazoline -4-carboxylate had higher inhibitory activity against Ca²⁺-uptake and higher in-secticidal activity than the R-isomer, but the difference was greater in theCa²⁺-uptake system.     

Synthesis,fungicidal activity and structure-activity relationships of a series of 1-(3-pyridyl)-1-substituted-but-3-yn-1-ols

A series of 1-(3-pyridyl)-1-substituted-but-3-yn-1-ols and some related compounds were synthesised and tested for antifungal activity against eight phytopathogenic fungi of different taxonomic classes. High activity was shown in particular against Sphaerotheca fuliginea on Cucumis sativus. The compounds containing aromatic substituents gave the best results, not only in protectant but also in systemic and eradicant tests. The quantitative structure-activity relationship suggests that steric effects play an important role in determining fungicidal activity.     

Structure-activity relationships of 1,2,3-benzothiadiazole insecticide synergists as inhibitors of microsomal oxidation

The activities of 47 substituted 1,2,3-benzothiadiazoles as inhibitors of microsomal epoxidation and/or hydroxylation in enzyme preparations from rat liver or armyworm (Spodoptera eridania) gut have been evaluated. Many were found to be effective inhibitors of microsomal oxidation, the most active being the 6-butyl and 6-propoxy derivatives with I₅₀ values of 4.9 × 10^?7 and 7.0 × 10^?7M, respectively, for the epoxidation reaction. Regression analyses have established that activity of the 5-, 6-, and 5,6-substituted compounds can be satisfactorily described in equations in terms of π², π, and σ whereas that of the 4-substituted derivatives depends on π and the steric parameter E₈.     

Quantitative structure—activity studies of some octopaminergic agonists against Periplaneta americana

The quantitative relationship between the structure of 2-(arylimino) thiazolidines (AITs), arylethanolamines (AEAs) and 2-(arylalkylamino)-2-thi-azolines (AATs) and their octopamine (OA)-agonist activities against the ventral nerve cord of American cockroach, Periplaneta americana L., was analysed using reported physicochemical parameters and regression analysis. The electronic nature of a substituent was the most important factor for AAT, followed by the hydrophobic effects: the more electron-donating and the more hydrophobic the substituent, the greater the activity. The hydrophobic nature of a substituent in AEA was the most important factor, followed by the steric effects: the more hydrophobic the substituent, the greater the activity. The more electron-donating the substituent of AIT, the greater the activity.