Inhibition of carotenogenesis by substituted diphenyl ethers of the m-phenoxybenzamide type

Diphenyl ethers exhibit different modes of action according to their chemical constitution. Diphenyl ethers of the m-phenoxybenzamide type, which were found to be effective on carotenogenesis resulting in an accumulation of colorless carotenoid precursors, mostly phytoene, indicative of inhibition of desaturation, are discussed. As seen with other carotenoid biosynthesis inhibitors, a concurrent loss of chlorophyll was observed as a secondary effect caused by the absence of protective carotenoids. In contrast to peroxidative p-nitrodiphenyl ethers like oxyfluorfen (2-chloro-4-trifluoromethylphenyl-3′-ethoxy-4′-nitrophenyl ether), the m-phenoxybenzamides assayed showed the same phytotoxic mode of action in the dark as observed when using heterotrophic Scenedesmus cultures. As expected, chlorophylls were not affected. The decrease of carotenoids was not due to their degradation but to inhibited carotenogenesis. Examination of carotenoid fractions show that the m-phenoxybenzamides, e.g., 3-(2,5-dimethylphenoxy)-N-ethylbenzamide, used here act similarly to 2-phenylpyridazinones like norflurazon [4-chloro-5-methylamino-2-(2-trifluoromethylphenyl)-pyridazin-3(2H)one]. All these inhibitors strongly decrease the α- and β-carotene content, while xanthophyll content is not lowered as much.     

Quantitative structure-activity relationships of insecticidal diphenyldichlorocyclopropanes

Neurophysiological activity of a series of aromatic-substituted 1,1-diphenyl-2,2-dichlorocyclopropanes (DCC analogs) in the induction of repetitive discharges in excised central nerve cords of the American cockroach was determined by an extracellular recording technique. Quantitative analysis using physicochemical parameters showed that variations in the activity were parabolically correlated with the van der Waals volume of aromatic substituents. Insecticidal activity of these compounds in the American cockroach under conditions where oxidative metabolic activity was inhibited by piperonyl butoxide was also determined. This was related to the repetitive nerve discharge activity, when transport factors were separated by using a hydrophobicity parameter. The analyses showed that the aromatic substituent effects on the neurophysiological activity as well as the relationship between insecticidal and neurophysiological activities are very close to those observed previously for DDT analogs including DDT, DDD, and prolan derivatives.     

Quantitative structure-activity relationships of pyrethroid insecticides

The structure-activity relationships of two congeneric series of pyrethroid insecticides, the methylbenzyl (1RS)-cis,trans-chrysanthemates tested against Musca domestica (houseflies) and Phaedon cochleariae (mustard beetles), and the (E)-4-aryl-3-chlorobut-2-enyl chrysanthemates and their corresponding 2,2,3,3-tetramethylcyclo-propanecarboxylates tested against M. domestica only, have been examined using multiple regression analyses and substituent constants. With M. domestica, different optimum partition values (π) were indicated for knockdown and toxicity; with P. cochleariae, an optimum π value for toxicity, similar to that for M. domestica, was obtained 24 h after application, but at later times the more lipophilic compounds were more effective. For the methylbenzyl chrysanthemates, a steric constraint associated with 3,5-dimethyl substitution reduced toxicity approximately five-fold. The influence on toxicity of geometrical isomerism and electronic effects are briefly discussed. Differences between the required polarities for knockdown and toxicity are attributed to variations in the binding affinities of pyrethroid molecules at the sites of action.     

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.     

Chemical structure-activity relationships of the inhibition of sterol biosynthesis by N-substituted morpholines in higher plants

Tridemorph and fenpropimorph as well as several related N-alkyl morpholines have been tested in vitro on the cycloeucalenol-obtusifoliol isomerase, a microsomal enzyme involved in higher plant sterol biosynthesis. The results showed that N-substituted morpholines inhibit powerfully the enzyme (I₅₀ = 0.4 μM for fenpropimorph). The following important molecular parameters of the inhibition could be determined: (i) the inhibitory capacity was probably related to the presence of a positive charge on the nitrogen atom, (ii) the length of the alkyl group was critical, with a maximum activity for n = 13 carbons in the case of a linear hydrocarbon chain, (iii) the presence of bulky substituents at the proximity of the nitrogen atom led to a strong decrease of the inhibitory power, (iv) in the fenpropimorph series where a chiral center is present at C-2 of the alkyl chain, a remarkable enantiomeric selectivity of the inhibition was observed, (v) the N-oxide derivative of fenpropimorph was shown to be as active as the parent compound. The N-alkyl morpholines have been also assayed on suspension cultures of bramble cells and led to a strong accumulation of 9β, 19-cyclopropyl- and Δ⁸-sterols. This result confirmed that the cycloeucalenol-obtusifoliol isomerase was a major target of the N-substituted morpholines and suggested that the Δ⁸ → Δ⁷-sterol isomerase was also a target for these chemicals. The molecular parameters implied in the in vivo accumulation of 9β, 19-cyclopropyl sterols were very similar to those resulting from the in vitro study. The chemical structure-inhibitory activity relationship of N-alkyl morpholines was discussed with respect to their fungicidal activity which has been described in a previous study [E. H. Pommer, Pestic. Sci. 15, 285 (1984)]. The comparison revealed that the better the inhibitory capacity on the cycloeucalenol-obtusifoliol isomerase was, the higher was the fungicidal activity in vivo.     

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 monoterpenoid binding activities to the housefly GABA receptor

BACKGROUND: Monoterpenoids are a large group of plant secondary metabolites. Many of these naturally occurring compounds have shown good insecticidal potency on pest insects. Previous studies in this laboratory have indicated that some monoterpenoids have positive modulatory effects on insect GABA receptors. In this study, the key properties of monoterpenoids involved in monoterpenoid binding activity at the housefly GABA receptor were determined by developing quantitative structure‐activity relationship (QSAR) models, and the relationship between the toxicities of these monoterpenoids and their GABA receptor binding activities was evaluated. RESULTS: Two QSAR models were determined for nine monoterpenoids showing significant effects on [³H]‐TBOB binding and for nine p‐menthane analogs with at least one oxygen atom attached to the ring. The Mulliken charges on certain carbon atoms, the log P value and the total energy showed significant relationships with binding activities to the housefly GABA receptor in these two QSAR models. CONCLUSIONS: From the QSAR models, some chemical and structural parameters, including the electronic properties, hydrophobicity and stability of monoterpenoid molecules, were suggested to be strongly involved in binding activities to the housefly GABA receptor. These findings will help to understand the mode of action of these natural insecticides, and provide guidance to predict more monoterpenoid insecticides. Copyright © 2012 Society of Chemical Industry     

Quantitative structure-activity relationships study of fungicidal O,O-diaryl S-ethyl phosphorothioates

The relationship between the structures of a series of O, O-diaryl S-ethyl phosphorothioates and their activity against five fungi has been analysed using physico-chemical parameters of the molecules such as hydrophobic R_M and electronic σ by means of multiple regression analysis. Both the hydrophobic and the electronic effects were found to have a significant contribution in determining the fungicidal activity of this series of compounds against all the test fungi.     

Quantitative structure-activity relationships of light-dependent herbicidal 4-pyridone-3-carboxanilides III. 3-D (comparative molecular field) analysis including light-dependent diphenyl ether herbicides

Using a set of representative members selected from 4-pyridone-3-carboxanilides and ortho-chlorinated diphenyl ethers exhibiting light-dependent herbicidal activity, we examined the three-dimensional structure-activity relationships quantitatively. The most stable conformation of each compound, regarded as the ‘active conformation’, was determined by either semi-empirical or ab initio molecular orbital calculations. With a hypothesis defining a common substructural skeleton between the two different compound series. each molecule was superimposed. We first analysed the structure-activity relationship using an index for the substructure shape similarity according to the superimposed conformations. After finding the relevance of the hypothesis, we examined the three-dimensional structure-activity relationship using the comparative molecular field analysis procedure. The results suggested that the two different series of compounds have a common region of the receptor site. The variations in the light-dependent herbicidal potency were governed by hydrophobicty and three-dimensional steric and electronic field parameters of molecules participating in the transport process and the interaction with the receptor site. The result was consistent with that derived from our previous quantitative analysis with the use of free-energy-related substituent parameters and the traditional regression procedure for a large number of pyridone-carboxanilides.     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 9. Calcium uptake inhibition in crayfish nerve cord and lobster axon homogenates in vitro by sunthetic pyrethroids

Twenty-five synthetic pyrethroids and related chemicals were assessed for their effects on the uptake of Ca²⁺ (as ⁴⁵Ca²⁺) by crude homogenates prepared from crayfish (Procambarus clarkii) nerve cords and 20 were assessed on the uptake by homogenates prepared from lobster (Panulirus japonicus) axons. A parabolic relationship was demonstrated between inhibition of Ca²⁺ uptake for this series of chemicals and lipophilicity (log P) in both species when tested at 5 μM. Optimal log P for maximal inhibition was located at about 6.6 and 84(±6)% inhibition was obtained with resmethrin. Compounds of higher or lower log P were either weaker inhibitors, not inhibitors or occasionally resulted in slightly increased levels of Ca²⁺ uptake. No direct correlations between the potential for the pyrethroids to inhibit Ca²⁺ uptake and the potential for these agents to increase the frequency of spontaneous discharges in crayfish nerve cords, to induce repetitive firing in American cockroaches, or the lethality to cockroaches or to any other neurophysiological or toxicity parameter could be established. It was concluded that although some synthetic pyrethroids are moderately potent inhibitors of Ca²⁺ uptake into nerve cord and axonic preparations (i.e., I₅₀ for trans-resmethrin equals 1 μM) this inhibition alone does not relate to the neurophysiological changes in isolated nerve preparations or to the toxicity of these agents in insects.     

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.     

Jack bean urease inhibition by substituted ureas

The increased use of urea fertilizer and substituted ureas herbicides, the implication of soil urease in the effectiveness of urea applied as fertilizer, makes necessary to investigate their relationship.All herbicides investigated, fenuron, monuron, diuron, linuron, siduron and neburon are urease inhibitors. The inhibition constant value depends on molecular groups on the urea skeleton. There is a linear relationship between the Hammett sigma values and log Ki for fenuron, monuron and diuron.The presence of a large hydrophobic group and of one or two chlorine—an electron withdrawing group—on the phenyl ring of the herbicides molecule influences the Ki value.The hypothesis is proposed that the enzyme molecule reacts with inhibitors by means of the oxygen atom of the carboxyl group in the substituted ureas.     

Quantitative structure-activity relationship of DDT analogs

A quantitative structure-activity relationship (QSAR) has been carried out for Phormia regina toxicity by a set of 24 p,p′-disubstituted analogs of DDT. The toxicity data are from the extensive studies of R. L. Metcalf. Preliminary examination of the data indicated that toxicity was parabolically related to molar refractivity, MR, of the ring substituents. This enabled parabolic regression to be evaluated. Multiple regression analysis relating toxicity and the substituent constants MR, Taft steric parameter (E_s), hydrophobicity (π), and polar effect (σ) showed that MR dominated the regression equations. The implication of these physicochemical properties in the interaction of DDT analogs with the receptor site is discussed.     

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.     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 1. Correlations between symptomatic and neurophysiological activities against American cockroaches

A number of substituted benzyl (1R)-trans-chrysanthemates and related compounds were synthesized. Their symptomatic activities in terms of levels which induce convulsions as well as cause death in American cockroaches were determined by injection with and without application of synergists as inhibitors of metabolism. The neuroexcitatory and neuroblocking activities were also determined in terms of minimum effective concentrations to induce repetitive train of impulses and conduction blockage, respectively, to central nerve cords excised from the cockroaches and immersed in Ringer's solution. Correlations between symptomatic and neurophysiological activities were analyzed quantitatively with the aid of molecular hydrophobicity parameter and regression analysis. Each symptomatic activity from which the effect of metabolism is eliminated was found to be analyzable by means of a linear combination of indices for two types of neurophysiological activity when the transport factor is separated by using the hydrophobicity parameter. A closer correlation was found between neuroblocking activity and the “convulsive” effect than between neuroexcitatory activity and the “convulsive” effect, whereas both neurophysiological effects operate together on the cockroaches resulting in paralysis and death.     

Studies into the action of the diphenyl ether herbicides acifluorfen and oxyfluorfen. Part II: The interaction with photosynthetic electron transport reactions

The effects of acifluorfen and oxyfluorfen on photosynthetic electron transport reactions of pea chloroplasts were compared with those induced by paraquat and monuron. Monuron inhibited electron flow between photosystems I and II, and paraquat acted as an electron acceptor for photosystem I, promoting superoxide formation by illuminated chloroplasts. Neither acifluorfen nor oxyfluorfen at concentrations up to 50 μM affected non-cyclic electron flow or promoted superoxide formation. Both herbicides were shown to repress ferredoxin-dependent NADP⁺ reduction by illuminated chloroplasts. Further experiments showed that, in the presence of ferredoxin-NADP⁺ reductase and chloroplast membranes maintained in the dark, p-nitro diphenyl ether (DPE) herbicides promoted the rate of ferredoxin-dependent oxidation of NADPH, implying that these herbicides can accept electrons from reduced ferredoxin. The interaction between acifluorfen, ferredoxin and chloroplast membranes was examined further by following the effect of this herbicide on the peroxidation of illuminated thylakoids. Lipid peroxidation was promoted by acifluorfen, although this effect was abolished if thylakoids were washed prior to use. The effect of washing could be reversed by adding exogenous ferredoxin. These data demonstrate that interaction of DPE herbicides with photosynthetic electron transport in the vicinity of ferredoxin is necessary for light-dependent herbicide activation.     

Quantitative structure-activity studies of substituted benzyl chrysanthemates: 7. Relationship between induction of repetitive discharges and effects on the action potential

The effects of substituted benzyl (1R)-trans-chrysanthemates and related compounds on the action potential of the crayfish giant axon were investigated using an intracellular microelectrode. The effects are broadly classified into three types: deceleration of the falling-phase of the action potential (type A), elevation of the depolarizing after-potential (type B), and the combination type (type C). The potency of the type A compounds to decelerate the rate of the falling-phase was determined in terms of the concentration required for reducing the rate to a specified degree. This potency was shown to correlate with the potency to induce repetitive discharges in the cockroach central nerve cord in terms of minimum effective concentration, which was determined previously. The potency of the types B and C compounds to elevate the after-potential was, however, not related directly with the cockroach nerve repetitive activity. The elevation of the after-potential is one of the critical factors but other effects such as a depolarization of the resting potential may be involved in determining the repetitive activity.     

Quantitative structure-activity study of herbicidal O-aryl O-ethyl N-isopropylphosphoramidothioates

The quantitative relationship between the structure of 46 O-aryl O-ethyl N-isopropylphosphoramidothioates and their herbicidal activity on the barnyard grass, Echinochloa cruss-galli, was analyzed using physicochemical parameters of the aryl substituents and regression analysis. We found that the hydrophobicity of the whole molecule and the position-specific steric and hydrophobic effects of substituents are important to the activity.