Physicochemical Substituent Parameters Research Articles

QSAR and mode of action studies of insecticidal ecdysone agonists†

A series of our SAR and QSAR studies of synthetic moulting hormone agonists, dibenzoylhydrazines (DBH), exhibiting insecticidal/larvicidal activity are reviewed in this article. We prepared a number of analogues where various substituents are introduced into the two benzene rings of DBH and measured their biological activity using various biological systems. Larvicidal activity was against larvae of the rice stem borer Chilo suppressalis and the moulting hormone activity was in terms of the stimulation of N-acetylglucosamine incorporation in a cultured integument system of the same insect species. Binding affinity to the ecdysone receptor was assayed with intact Sf-9 cell lines in which the ADME processes are negligible as well as using receptor proteins obtained by in vitro translation of the responsible cDNA cloned from cell-free preparation of integumentary tissue of C. suppressalis. Variations in the biological activity indices were either correlated between two types of activity or correlated using physicochemical molecular and substituent parameters in terms of the classical QSAR. Comparisons among correlations and with recently revealed X-ray crystallographic findings clearly indicate the physicochemical meaning of parameters significant in the correlation equations to help understanding molecular mechanism of the moulting hormonal action. †Presented at the 12th International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology (QSAR2006), 8--12 May 2006, Lyon, France.

Quantitative structure-activity relationships of imidacloprid and its analogs with substituents at the C5 position on the pyridine ring in the neuroblocking activity

Two nerve activities of imidacloprid analogs with various substituents at the 5-position of the pyridine ring were measured: the conduction blockage in the excised central nerve cord of the American cockroach, and the binding inhibition of a radioligand, [3H]imidacloprid, to the membrane preparation of housefly-head homogenates. Neuroblocking activity was quantitatively analyzed using physicochemical substituent parameters. The greater the electron-releasing resonance effect, the higher the activity. The introduction of sizable and alkoxy substituents was unfavorable. The nerve-binding activity of the tested compounds was linearly related to the neuroblocking activity with one exception. The higher the binding activity, the higher the blocking activity. © Pesticide Science Society of Japan

Quantitative structure-fungicidal activity relationships ofN-(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.

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 (Es). 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

Synthesis and Structure-Activity Relationships for the Fungicidal Activity ofO,O-bisarylsec-butylphosphonates

Sixteen O,O-bisaryl sec-butylphosphonates have been synthesised by condensing sec-butylphosphonyl dichloride with substituted phenols. The compounds were tested against two phytopathogenic fungi, Rhizoctonia bataticola and Helminthosporium oryzae. The most active compound against R. bataticola is O,O-bis(3-methylphenyl) sec-butylphosphonate (ED 50 29.56 mg litre -1 ) and against H. oryzae, O,O-bis(2-chlorophenyl) sec-butylphosphonate and its para-chloro analogue (ED 50 0.14 and 0.13 mg litre -1 respectively). Quantitative structure-activity relationships on the fungicidal activity have been analysed by means of multiple regression analysis using physicochemical substituent parameters. Electronic parameters viz., σ and F have expressed significant variability in fungitoxicity against both the fungi, viz. R. bataticola and H. oryzae. Hydrophobic and steric parameters are also found to be important in the correlation studies.

Larvicidal Effects of Benzoylphenylureas Against the Lesser Mealworm (Coleoptera: Tenebrionidae): Quantitative Structure-Activity Relationships2

Larvicidal activity of a congeneric set of N-2-halo- (and 2,6-dihalo) benzoyl-N-phenylureas were determined in in vivo tests against the lesser mealworm, Alphitobius diaperinus (Panzer). Substituent modifications were made in both the benzoyl and anilide portions of the molecule. Linear regression analysis was used to derive quantitative structure-activity relationships (QSAR) from LC50 and LC99 values and a series of physicochemical substituent parameters. The analysis resulted in two significant single parameter regression equations selecting Hammett σp constant as the only relevant chemical descriptor and rejecting the other descriptors as insignificant. Penfluron and 2,6-difluoro-N-[[[4-(trifluoromethoxy) phenyl]amino]carbonyl]benzamide were potent larvicides in these tests and exceeded the effectiveness of diflubenzuron and triflumuron.

Quantitative structure—activity relationships of insecticidal pyrazolines

AbstractMethyl 3‐(4‐chlorophenyl)‐4‐methyl‐1‐[N‐(4‐substituted pheny1)carba‐moy1]‐2‐pyrazoline‐4‐carboxylates and related compounds were prepared. Their convulsant activity was determined as the minimum dose required to bring about the symptom within 1 h after injection against male adult American cockroaches, Periplaneta americana (L.). Insecticidal activity with metabolic inhibitors for oxidation and hydrolysis was measured 24 h after injection of the test compounds. Variations in each of the activities were analysed by using physicochemical substituent parameters and regression analysis. The findings indicated that the greater the hydrophobicity and the more the electron‐withdrawing property of the substituents, the higher were the activities. Variations in each of the two activities were parabolically related to the STERIMOL width parameter with an optimum value of about zero.

Quantitative Structure-Hydrophobicity and Structure-Activity Relationships of Antibacterial Gramicidin S Analogs

The structure–hydrophobicity–antibacterial activity relationships of gramicidin S and its analogs retaining a β-pleated sheet structure were examined quantitatively with physicochemical substituent and molecular parameters using regression analyses. Variations in their apparent hydrophobicity in an octanol/buffer (pH 7) system, logP(O/W), were analyzed in terms of the “effective” hydrophobicity and steric parameters of side chain substituents of residues at certain positions in the molecule; however, some of the conformational factors have not been fully defined. For the partitioning into liposomes and the growth inhibitory activity against species of Gram-positive bacteria, the logP(O/W) value simulated the hydrophobic effects of gramicidin S and its analogs better than substituent parameters. The side chain hydrophobicity was assumed to work together with effects attributed to variations in the entire cyclic peptide structure including conformational components undefined in the structure–logP(O/W) analysis in these activities.

Quantitative Structure-Activity Studies of Pyrethroids 31. Insecticidal Activity of meta-Substituted Benzyl Esters of 1-( para-Ethoxyphenyl)-2,2-dichlorocyclopropane- and -2,2,3,3-tetrafluorocyclobutane-1-carboxylic Acids

Esters of racemic 1-( para-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane- and 1-( para-ethoxyphenyl)-2,2-dichlorocyclopropane-1-carboxylic acids with a number of meta-substituted benzyl alcohols were prepared. Their insecticidal activity against American cockroaches was measured by injection under synergistic conditions with inhibitors of oxidative and hydrolytic metabolic mechanisms. The insecticidal activity of the tetrafluorocyclobutanecarboxylates was usually more potent than that of the corresponding dichlorocyclopropanecarboxylates, although the degree was not uniform. Variations in the insecticidal potency were quantitatively examined using physicochemical substituent and structural parameters and regression analyses. The introduction of substituents possessing a benzene ring per se was favorable for the activity when factors due to physicochemical and steric features were equal among analogs in the two series of esters. The less bulky the substituents, the higher the insecticidal potency of both series, when the effect of the benzene ring was separated. For F 4-cyclobutanecarboxylates, the hydrophobicity of substituents augmented the potency. In each series, the effect of substituents introduced into the phenoxy-benzene ring as the component of the primary substituent was such that there is an optimum hydrophobicity for the interaction of this local moiety with a hypothetical receptor. The para-substituted phenoxy groups were more favorable than ortho- and meta-substituted phenoxy groups.

Neurophysiological Effects and Quantitative Structure-Activity Analyses of Insecticidal Silaneophanes

Silaneophanes containing a quaternary silicon connected to variously substituted phenyl groups were shown to prolong the sodium residual and tail currents in the crayfish giant axon under voltage clamp conditions, sharing characteristics common to conventional pyrethroids. Insecticidal activity of these compounds was measured against American cockroaches. Variations in the insecticidal activity measured under conditions to inhibit the oxidative metabolic mechanism were analyzed quantitatively. It was found that insecticidal activity was linearly related to the crayfish tail-current prolongation activity when the transport factors of compounds were allowed for by use of a hydrophobicity parameter. The higher the tail-current prolongation activity, the higher the insecticidal activity. Variations in the insecticidal activity were also correlated with physicochemical substituent parameters, indicating that the longer the substituents on the benzene ring, the higher the activity. There was an optimum in the hydrophobicity of the substituents, probably related to factors involved in the transport process.

Quantitative Structure-Activity Studies of Insect Growth Regulators: X. Substituent Effects on Larvicidal Activity of 1-tert-Butyl-1-(2-chlorobenzoyl)-2-(substituted benzoyl)hydrazines against Chilo suppressalis and Design Synthesis of Potent Derivatives

The larvicidal activity of 1-tert-butyl-1-(2-chlorobenzoyl)-2-(substituted benzoyl)hydrazines was measured against the rice stem borer (Chilo suppressalis) in the presence of piperonyl butoxide, an inhibitor of oxidative metabolism. Variations in the activity were quantitatively examined by use of physicochemical substituent parameters and regression analysis. The results indicated that the hydrophobicity of substituents is favorable in general but the bulkiness of substituents is unfavorable position-specifically. The most favorable substitution pattern is the para substitution with lower alkyls and halogens. Compounds in which substitution patterns are simultaneously optimized in two benzene rings in the molecule were designed and prepared according to the present and previous quantitative analyses. Some of them, including 1-tert-butyl-1-(3,5-dichloro- and 3,5-dimethylbenzoyl)-2-(4-ethylbenzoyl)hydrazines, the second being RH-5992, were about 20-30 times as larvicidal as the unsubstituted compound, RH-5849, against the rice stem borer.

Quantitative analysis of electron transport inhibition of rat-liver mitochondrial cytochrome bc1 complex by nitrophenols

A series of nitrophenolic electron transport inhibitors (2- sec-butyl-4-nitro-6-substituted phenols and 2- sec-butyl-4-substituted-6-nitrophenols) of rat-liver mitochondrial cytochrome bc 1 complex (cyt. bc 1 complex) was synthesized. To obtain information on the three-dimensional structure of the ubiquinone redox site of cyt. bc 1 complex, the structure-inhibitory activity relationship was examined by regression analysis using physicochemical substituent parameters. The inhibitory activity increased as the hydrophobicity and the electron-withdrawing ability of the 4- and 6-substituents increased. These results indicated that hydrophobic interaction between the inhibitor molecule and the binding domain should be important and that an anionic form of nitrophenols may be the active form at the binding domain. Hydrogen-bond-acceptable 4-substituents such as methoxy and nitro groups, but not cyano group, were favorable to the inhibitory activity. This result, along with the fact that phenolic OH group was essential for the activity, suggested that nitrophenols occupy the ubiquinone redox site by forming two hydrogen-bond bridges as proposed for natural ubiquinone binding. Although a cyano group is hydrogen-bond-acceptable, hydrogen-bond formation between the 4-cyano group and the binding domain was not suggested. This result and molecular orbital calculation studies on electrostatic potential of the inhibitors suggested that hydrogen-bond donating residue may be not located in the region where the rod-like cyano ( C≡N ) bond directs.

Analysis and prediction of hydrophobicity parameters of substituted acetanilides, benzamides and related aromatic compounds

AbstractThe partition coefficient P in the 1‐octanol/water system was analyzed for a great number of multisubstituted benzenes of ecotoxicological importance consisting of acetanilides, benzamides, nitrobenzenes, and anisoles having various substitution patterns in terms of the Δ log P (log P – log P[unsubstituted benzene]) quantitatively with free energy‐related physicochemical substituent parameters. The analyses showed that the stereoelectronic effects of ortho, meta, and para substituents on the relative solvation of individual polar groups capable of hydrogen bonding with the partitioning solvents are very important in determining the variations in the log P value. The effects were additive in the set of complicated multisubstituted benzenes, leading to a correlation equation represented by a linear combination of terms of hydrophobic, electronic, and steric parameters summed up over substituents. It was suggested that the procedure be extended to analyze and predict the log P value of any multiply substituted benzenes.

Quantitative analysis of structure-toxicity relationships of substituted anilines by use of Balb/3T3 cells

The acute toxicities of 24 substituted anilines in terms of 50% inhibition concentrations (150) for viability of cells and their adenosine triphosphate (ATP) content were measured with monolayer cultures of Balb/3T3 cells. The quantitative relationship (QSAR) was analyzed for the pI50 (viability) value with physicochemical substituent parameters. The pI50 (viability) value of substituted anilines was parabolically related with log P, P being the 1-octanol/water partition coefficient, where electronic and hydrogen bonding effects were separately considered. There was a good correspondence between pI50 values for cellular viability and ATP content. None of the test compounds, however, showed any specific depletion of cellular ATP content, suggesting that substituted anilines do not specifically damage the energy metabolism of the cells.

Quantitative structure-activity studies of benzoylphenylurea larvicides: VIII. Inhibition of N-acetylglucosamine incorporation into the cultured integument of Chilo suppressalis Walker

The inhibition by N-(2,6-disubstituted benzoyl)- N′-(4-substituted phenyl)urea larvicides of the incorporation of N-acetyl-[1- 14C]glucosamine, the precursor of chitin, into cultured fragments of the integument of Chilo suppressalis Walker larvae was measured in terms of the median inhibitory concentration with and without metabolic inhibitors. Variations in the activity index were quantitatively analyzed with physicochemical substituent parameters and regression analysis. The variations in the inhibitory activity of compounds in which ortho substituents on the benzoyl moiety were varied with a fixed substituent in the anilide moiety corresponded with the variations in their larvicidal activity. After separate consideration of the hydrophobic effect participating in transport processes, substituents in the anilide moiety showed peculiar electronic effects that depended upon the situation. Without an inhibitor of oxidative metabolism, the greater the inductive component of the electron-withdrawing property, the greater was the inhibition. This pattern resembled that found in earlier observations of larvicidal activity. With the inhibitor, the greater the total electrondonating property, including both inductive and resonance components, the greater was the inhibition. These results showed that the regular electron-donating effect of substituents in the anilide moiety is intrinsically favorable to the inhibition. Such an electronic mechanism as free-radical intermediate formation at the anilide moiety in oxidative metabolism may not be eliminated completely under the conditions used here for larvicidal activity measurement even with an inhibitor of oxidative metabolism.

Quantitative structure—activity relationships of light‐dependent herbicidal 4‐pyridone‐3‐carboxanilides I. Effect of benzene ring substituents at the anilide moiety

AbstractA 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 (Es) of the ortho‐substituents. The Es 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 (Es) 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 pyrethroids: 28. Type differentiation of action-potential changes in crayfish giant axons caused by substituted benzyl chrysanthemates and pyrethrates

The neurophysiological actions of variously substituted benzyl (1R)-trans-chrysanthemates and (1R)-trans-(E)-pyrethrates on the membrane potential of crayfish giant axons were observed by use of an intracellular microelectrode. The compounds were classified into three types according to their effects: deceleration of the falling phase of the action potential (type A), elevation of the depolarizing afterpotential (type B), and a combination of these effects (type C). The effects of substituents on the benzyl-benzene ring of the alcohol moiety on the type differentiation of actionpotential changes were examined by such statistical procedures as linear discriminant and logistic regression analyses with physicochemical substituent parameters. Logistic regression analysis was especially efficient in type classification. The most important substituent factors governing the type differentiation were steric bulk and electronic property. With increases in the bulkiness of substituents in terms of the van der Waals volume, the compound tended to change in its effects in the order of type A, type C, and type B. The greater the electron-withdrawing property, the greater was the tendency of compounds to be classified as type B.

Hydrophobicity Parameter of Diazines. II: Analysis and Prediction of Partition Coefficients of Disubstituted Pyrazines

The partition coefficient in a 1-octanol–water system (log P) of a number of disubstituted pyrazines was measured. The increment produced by introduction of two substituents [π(disubst)PR] was analyzed in terms of the πvalue of substituents in monosubstituted pyrazine (π2PH) and other physicochemical substituent parameters, considering electronic and steric intractions operating bidirectionally between individual partners of substituents and aza-functions. When the substituents were nonamphiprotic and their steric interaction was not significant, the π (disubst)PR value was approximately predicted by the summation of the π2PR values of corresponding substituents. For amphiprotic substituents, a correction for electronic interactions between the two substituents was needed but it was less important than that required in disubstituted benzenes. The results suggest that the difference in the π values between disubstituted pyrazine and benzene systems was mostly governed by that between monosubstituted pyrazine and benzene systems with component substituents. In 2,6- and 2,3-disubstituted derivatives, bulky substituents had steric effects in such a way that the log P value was lowered.

Quantitative analysis with physicochemical substituent and molecular parameters of uncoupling activity of substituted diarylamines

Variations in the uncoupling potency of a series of substituted diphenyl- and phenylpyridylamines with rat-liver mitochondria were analyzed quantitatively by regression analysis by use of two physicochemical parameters, log P (M/W) and log K m A . P (M/W) is the partition coefficient of compounds for incorporation into mitochondria from the aqueous phase and K m A is the acid dissociation constant in nonionic micellar system. The results of the analysis were similar to those observed previously for phenolic uncouplers, showing that the incorporation of compounds into the mitochondrial phase and a certain balance between neutral and ionized forms in the membranous phase were significant factors in governing the uncoupling potency. The findings were in accord with the hypothesis that the acidic uncouplers act primarily by working as protonophores in the inner mitochondrial membrane. In contrast to results obtained with phenols, however, the variations in the steric effect of the ortho substituents in shielding the negatively charged center of the ionized form did not significantly affect variations in the uncoupling potency of the diarylamines studied here.