Structure-activity relationships among the imidazolinone herbicides

The structure of the imidazolinone herbicides consists of three distinct moieties: the imidazolinone ring, the carboxylic acid and the backbone. The effect of changes in each of these on herbicidal activity, crop selectivity and AHAS enzyme inhibition has been studied. Though both whole-plant and enzyme activity were drastically affected by changes in the carboxylic acid or imidazolinone ring portions of the molecule, a variety of backbones and of substituents on the backbones afforded good activity. Methyl-isopropyl was found to be the best combination of substituents on the imidazolinone ring. While pyridine backbones generally gave the most active herbicides, benzene backbones led to the strongest enzyme inhibition. A QSAR study in the pyridine series generated two equations which proved useful for guiding the analog program toward the synthesis of potent heteropyridyl compounds. Selectivity in wheat is dependent upon differences in the rate of metabolism of key groups. Rapid metabolism of either the imidazolinone ring or backbone alkyl groups occurs rapidly in soybeans compared with susceptible weeds.     

Structure-activity relationships in fungitoxicants related to triforine and chloraniformethan. I. Synthesis and fungitoxicity to Erysiphe graminis on barley

Seventy analogues of chloraniformethan and triforine were prepared and tested for activity against barley powdery mildew caused by Erysiphe graminis. Structural variations, including replacement of the trichloromethyl, formamido, 3,4-dichloroanilino or piperazin-1,4-diyl groups, yielded information concerning the structural characteristics required for activity in leaf-spray or root-drench tests, and it appears that the XCHNHCO grouping (where X=substituted nitrogen, oxygen or sulphur) is a prerequisite for activity.     

Fenbendazole. II. Biological properties and activity

Fenbendazole has a broad spectrum of activity against immature and adult helminths of the intestinal tract and lungs at an oral dose of 5–7.5 mg/kg. This compound has a wide margin of safety in domestic animals without teratogenic side effects. Data are given on metabolism, mode of action and excretion.     

Structure-activity relationships in a group of imidazole-1-carboxamides

Detailed structure-activity studies in a series of substituted imidazole-1-carboxamides culminated in the synthesis of N-alkyl-N-phenoxyalkyl substituted compounds and, eventually, prochloraz, a compound shown to give excellent broad-spectrum disease control in cereals. Subsequently, evidence was obtained which suggests that its mode of action is through the inhibition of ergosterol biosynthesis or, more specifically, through inhibition of sterol C-14 demethylation.     

Structure-activity relationships of insecticidal amides from Piper guineense root

The structure-activity relationships between five amides previously isolated from the root extract of Piper guineense Schum and Thonn were studied. The methyl-terminated amides, pellitorine and kalecide, were found to be more polar and caused higher knockdown, but showed less lethal action against insects than their methylenedioxyphenyl-terminated counterparts, pipercide and guineensine. Guineensinamide showed weak activity and this was correlated with higher unsaturation and the presence of a pyrrolidyl group in the molecule. There was an association between the polarity of the amides and the recovery of the insects from their effects, much more recovery being observed with the methylterminated than with the methylenedioxyphenyl-terminated amides. Electrophysiological investigations of the effects of pellitorine and pipercide on miniature excitatory postsynaptic potentials (MEPSPs) from the locust retractor unguis nerve-muscle preparation showed that the amides caused a reduction in both the frequency and amplitude of MEPSPs, pipercide being between 100 and 1000 times more effective than pellitorine. An action of the amides on presynaptic transmission is suggested. The effects of pipercide and pellitorine on the isolated nerve-muscle preparation were correlated with the symptoms of poisoning at the whole animal level.     

Structure-activity relationships in fungitoxicants related to triforine and chloraniformethan. III. A quantitative hansch analysis

Quantitative structure-activity relationships in several series of fungitoxic N-(1-substituted-2,2,2-trichloroethyl)formamides and bis[1-(2,2,2-trichloroethyl)formamides] were investigated by the Hansch method, employing partitioning data determined by reversed-phase thin-layer chromatography and electronic parameters calculated by the Hückel Molecular Orbital method. The activity of compounds applied as root-drenches against Erysiphe graminis on barley correlated with their partitioning properties alone, but electronic properties of the aromatic derivatives were also influential in leaf-spray tests. Possible factors governing the activity of the compounds are discussed. It is tentatively proposed that the biologically active centre of triforine and related aliphatic compounds includes the XCHNHCO grouping (where X = heteroatom), whereas that of chloraniformethan and its aryl analogues incorporates the grouping RXCHNHCO (where RX = a conjugated system capable of accepting pi-electrons from an electron donating receptor).     

Structure-activity relationships in a series of new antifungal nitroalcohol derivatives

The structure-antifungal activity correlations of 23 new nitroalcohol derivatives (1-substituted-2-nitropropane-1, 3-diols, their ethers and esters) were investigated using a generalised quantitative structure-activity relationships (QSAR) method, combining Golender and Rozenblit's logico-structural approach and the Free-Wilson and Hansch analyses. Based on results obtained from principal component analysis, the in-vitro activities against Helminthosporium sativum, the inhibition of germination and of growth could be assumed to be governed by a common mechanism. It is suggested that the antifungal activity of the compounds studied is determined mainly by the presence or absence of an aromatic ring (unsubstituted, or bearing a hydrophobic group that is small in bulk and electron-attracting) at position 1, of a (potential) double bond between carbon atoms 1 and 2, and of an acyloxy group at position 3. Among these factors, the double bond seems to be the most important, and the mechanism of the antifungal action is probably dependent on the reactivity of this bond towards thiol groups of endogenous substances.     

Structure-activity relationships of pyrethroids based on direct action on nerve

The structure-activity relationships of 30 synthetic pyrethroids have been studied by measurements of their direct action on isolated crayfish nerve cord. The concentrations of pyrethroids used to increase the frequency of spontaneous discharges to 200% of the control (NS₂₀₀), those to decrease the frequency back to the control level, and those to further decrease the frequency to 10% of the control were measured as indexes of the nerve action. These values did not necessarily run parallel with those for the lethal dose 50 or the knock-down 50. Large differences in NS₂₀₀ were found among optical isomers of tetramethrin and phenothrin, and there was a synergism with respect to the nerve stimulating action between (+) and (?) forms of tetramethrin. (+)-trans-Permethrin was unique in that it exhibited a potent insecticidal action with a very weak nerve action. It is necessary to compare the direct action on the target site for the purpose of establishing the true structure-activity relationships of synthetic pyrethroids.     

Structure-activity relationships in fungitoxicants related to triforine and chloraniformethan. II. Redistribution on barley and marrow seedlings

Structural factors governing the redistribution of triforine, chloraniformethan and related compounds on barley and marrow leaves have been investigated. Replacing the 3,4-dichloroanilino or piperazino groups gave compounds which in general underwent acropetal movement, and the degree of redistribution was greatest with the more hydrophilic compounds. Replacing the trichloromethyl by other halogenomethyl groups, or replacing the formyl by other keto groups, gave compounds which were not redistributed. No significant redistribution of any compound in the vapour phase was observed.     

Structure-activity relationships in triorganotin biocides: The influence of the anionic radical

Bioassay data are reported for seven triorganotin compounds (R₃SnX), in which R=phenyl, cyclohexyl, or 2-methyl-2-phenylpropyl, and × is the anionic form of the organic chelating ligands quinolin-8-ol, quinoline-8-thiol, 1,3-diphenylpropane-1,3-dione, or 3-hydroxyflavone, when tested against an organophosphorus-resistant species of the two-spotted spider mite (Tetranychus urticae), the potato blight fungus (Phytophthora infestans), and the vine downy mildew fungus (Plasmopara viticola). The relationship between the activity and the co-ordination number of the tin atom is discussed, and it is shown that the anionic group × can, in some instances significantly affect the biological properties.     

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.     

Structure-activity relationships of triazinone herbicides on resistant weeds and resistant Chlamydomonas reinhardtii

Weeds resistant to the s-triazine herbicide atrazine also show resistance to the triazinone herbicide metribuzin. However, with highly lipophilic triazinones, thylakoids isolated from atrazine-resistant Amaranthus retroflexus (mutation at position Ser₂₆₄ of the photosystem II D-1 reaction centre protein) in general show a higher pI₅₀ value in photosystem II electron transport than those from the wild type (i.e. negative cross-resistance; ‘supersensitivity’). A quantitative structure–activity relationship (QSAR) can be established, wherein the lipophilicity of the compound plays a major role. In in-vivo experiments, it was found that the triazinone DRW2698 killed resistant Amaranthus retroflexus and Chenopodium album whereas the wild type was almost unaffected. Triazinones were further investigated in five different mutants of Chlamydomonas rheinhardtii (mutations in the D-1 protein at positions Ser₂₆₄, Ala₂₅₁, Leu₂₇₅, Phe₂₅₅, and Val²¹⁹). Inhibitory activity of all triazinones was generally enhanced in the Phe₂₅₅ mutant but decreased in the Val₂₁₉ mutant. In the other mutants, biological activity was decreased when position 3 of the triazinone was substituted by CH₃, OCH₃, SCH₃, NHCH₃ or N(CH₃)₂. However, negative cross-resistance was again observed when this position was occupied by free thiol. It is therefore suggested that these two groups of triazinones orient themselves differently within the herbicide binding niche of the photosystem II D-1 protein.     

Structure-activity relationships of pheromonostasis induced by ACCase-inhibitor herbicides in the moth Helicoverpa armigera

Many moth sex pheromone blends are derived from fatty acids and their production is regulated by a Pheromone Biosynthesis Activating Neuropeptide (PBAN). In prior work we showed that the herbicide Diclofop-acid, an acetyl-coenzyme A carboxylase (ACCase) inhibitor, inhibits PBAN-induced sex pheromone production in vitro. In this work we extend our study showing that several other herbicides, belonging to the 2-aryloxyphenoxypropionate (‘FOP’) and the cyclohexandione-oxime (‘DIM’) families significantly inhibit pheromone production by adult females whilst survival is unaffected by treatment. Enzyme activity in vitro and kinetic analysis revealed a K_m of 0.35 μM with K_i values of 0.1 and 0.28 μM due to Tralkoxydim and Diclofop inhibition, respectively. Inhibitory activity on PBAN-induced pheromone production by all herbicides tested revealed a potency order: Tralkoxydim > Clodinafop > Cycloxidim > Haloxyfop > Diclofop > Fenoxaprop > Fluazifop > Quizalofop, Quizalofop being inactive. Differences in inhibition efficiencies may be attributed to different binding sites on the enzyme or to the polarity and solubility of these compounds.     

Structure-activity relationships of carboxamide fungicides and the succinic dehydrogenase complex of Cryptococcus laurentii and Ustilago maydis

The systemic fungicide, carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) and a variety of carboxamide compounds exhibit a marked specificity for Basidiomycete fungi. This unique specificity resides in the mitochondrial succinic dehydrogenase complex (SDC) of sensitive Basidiomycetes such as Ustilago maydis, the corn smut fungus. The present study examines in detail the structure-activity relationships of 93 carboxamide compounds and the SDC of two carboxin-sensitive organisms, U. maydis and a Basidiomycetous yeast, Cryptococcus laurentii. It has been possible to elucidate substantially the requirement in molecular structure needed for inhibition of the mitochondrial SDC. With few exceptions, a good correlation exists between the inhibitory activity of carboxamides towards the SDC of U. maydis and C. laurentii and the inhibition of growth of carboxamide-sensitive fungi, both in vitro and in vivo on the diseased plant. The structure-activity results were used as a basis for the synthesis of new, fungicidally-active carboxamides. The compounds found to be most active against the mycelial growth of Rhizoctonia solani were also tested on spore germination or mycelial growth of non-Basidiomycete fungi. Three carboxanilides (3-methyl-thiophene-2-carboxanilide, 3′-methyl-2-methylbenzanilide and 3′-methyl-2-ethylbenzanilide) had a fungitoxic spectrum which extended beyond Basidiomycetes. The spectrum of fungicidal activity of carboxanilides appears to be altered not only by substitution in the aniline ring, but by the nature of the ring attached to the carbonyl. No correlation was found between the inhibitory activity of oxathiins and benzanilides and their calculated partition coefficients.     

Structure-activity relationships in a group of azoles,with special reference to 1,3-dioxolan-2-ylmethyl derivatives

Substituted imidazoles and substituted 1,2,4-triazoles are active to varying degrees in the control of fungi pathogenic to plants, animals and man. The relationship between chemical structure and their antifungal activity, both in-vitro and in-vivo, is reviewed.     

Structure-activity relationships of 1,2,3-benzothiadiazoles as synergists for carbaryl against the house fly (Musca domestica)

Fifty six 1,2,3-benzothiadiazoles and related compounds were evaluated as carbaryl synergists against the house fly (Musca domestica). Many of these were excellent synergists, the most active being those containing various combinations of halogen, alkyl, or alkoxy substituents in the 5- and/or 6-positions of the ring.Regression analysis on the data from 14 compounds for which substituents constants were available established that synergistic activity can be satisfactorily described by equations in terms of the hydrophobic bonding constant (π) and the homolytic free radical constant (σ ·).The results with compounds related to the 1,2,3-benzothiadiazoles suggest that synergistic activity is associated primarily with the diazosulfide moiety.     

Porphyric insecticides. IV: Structure-activity study of substituted phenanthrolines

The porphyric-insecticide-modulating activities of 1,10-phenanthroline and eight of its analogs were investigated. The insecticidal efficacy of these compounds was closely associated with their ability to enhance the conversion of exogenous δ-aminolevulinic acid (ALA) to protoporphyrin IX (Proto). As observed for photodynamic herbicidal effects in plants, the presence of nitrogen atoms at positions 1 and 10 of the macrocycle was essential for porphyric insecticidal activity. This was evidenced by the very limited activity of phenanthrene, in which positions 1 and 10 are occupied by carbon instead of nitrogen atoms. On the other hand, enhancement of Proto formation and porphyric insecticidal activity were maintained following methyl, chloro and nitro group substitution at the periphery of 1,10-phenanthroline. In contrast, Proto levels and photodynamic toxicity were reduced by hydroxy and phenyl substitution at the same positions. Benzyl substitution at the 2–3 and 8–9 positions was also inhibitory. Quantitative structure-activity calculations suggested a relationship between peripheral group substitution and physicochemical properties of the substituted compounds. Electron density changes in 1,10-phenanthroline and its analogs that appeared to be related to reduced efficacy included (a) appearance of positive charge-binding volumes at positions 4 and 7 of the 1,10-phenanthroline macrocycle, which flanks positive charge-repelling volumes, (b) a dramatic increase in superdelocalisability (i.e. electron density) over some unoccupied molecular orbitals, and (c) electronic charge at positions 1 and 10 of the macrocycle. Large increases in van der Waals volumes also exerted negative effects on insecticidal efficacy.     

Thiophene carboxamide fungicides: Structure-activity relationships with the succinate dehydrogenase complex from wild-type and carboxin-resistant mutant strains of Aspergillus nidulans

Carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) and the thiophene compound 3-methylthiophene-2-carboxanilide (I), inhibit succinate oxidation (succinate-ubiquinone reductase; complex II) in mitochondria from a wild-type strain and three mutant, carboxin-resistant strains of Aspergillus nidulans. Studies by White et al. [Pestic. Biochem. Physiol. 9, 165–182 (1978)] showed that certain oxathiin carboxamide structures were selectively active against particular mutated succinate dehydrogenase complexes (SDCs) of A. nidulans, significantly lowering the level of resistance. Although no oxathiin carboxamides were found to be negatively correlated to carboxin with respect to their effect on SDCs from wild-type and mutant strains of A. nidulans, several could distinguish between moderately and highly carboxin-resistant SDCs and, as shown in the present study, between the two non-allelic highly carboxin-resistant mutants cbx B-28 and cbx C-34. Variation in the molecular structure of thiophene carboxamides can also affect the phenotypic expression of mutations to carboxin resistance in the SDC of A. nidulans, with certain structures being capable of differentiating between moderately and highly carboxin-resistant mutated SDCs. With a moderately carboxin-resistant mutant, cbx A-17, a wide structural variety of thiophene carboxamides, e.g., the 2′-methyl, 2′-benzoyl, 3′-phenoxy, 4′-nbutyl and the N-nhexyl derivatives of (I), did exhibit negative activity correlation to the parent anilide (I). However, with the possible exception of the 4′-nbutyl and 4′-noctyloxy analogs of (I), thiophene carboxamides showed no negative activity correlation to carboxin or (I) for the highly carboxin-resistant mutants cbx B-28 and cbx C-34. As with carboxin-resistant mutants of Ustilago maydis [Pestic. Biochem. Physiol. 14, 26–40 (1980)], molecular selectivity for mutated carboxin-resistant SDCs of A. nidulans can be markedly influenced by substitution of an oxathiin with a thiophene heterocyclic ring. None of the thiophene carboxamides were considerably toxic to mycelial growth of the wild-type and carboxin-resistant strains of A. nidulans with permeability rather than affinity for the SDC appearing to be the limiting factor. For certain derivatives such as the 5-amino analog of (I), SDC activity and cell growth were inhibited similarly. Several thiophene carboxamides [2′-phenyl, 4′-phenoxy, and N-ndecyl analogs of (I)] showed specificity for the highly carboxin-resistant mutants cbx B-28 and cbx C-34. Thiophene carboxamide structures have been identified which inhibit spore germination of non-Basidiomycete plant pathogens, particularly Phytophthora infestans and Verticillium dahliae. In vivo experiments with late blight (P. infestans) on tomato plants have shown that a few thiophene carboxamides, e.g., the 3′-nbutyl analog of (I) give satisfactory protectant activity.     

Thiophene carboxamide fungicides: Structure-activity relationships with the succinate dehydrogenase complex from wild-type and carboxin-resistant mutant strains of Ustilago maydis

A variety of thiophene carboxamide compounds have been synthesized and tested on the succinate dehydrogenase complex (SDC) in mitochondria from a wild-type strain and carboxin-resistant strains of Ustilago maydis (corn smut). The site of action of thiophene carboxamides is identical to that of carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) and thenoyltrifluoroacetone, that is, the succinate-ubiquinone reductase (complex II) span in the mitochondrial electron transfer chain. This investigation reveals new molecular structures which are strong inhibitors of wild-type and carboxin-resistant SDCs. The 5-amino analog of the parent anilide, 3-methylthiophene-2-carboxanilide (I), proved to be an especially potent inhibitor of the wild-type SDC (I₅₀, 0.019 μM). Analogs of (I) such as 4′-carboethoxy, 4′-nbutyl, 4′-phenyl, and 4′-benzoyl were negatively correlated in activity to the carboxanilide (I) with respect to resistance level. A number of structures showed considerable selectivity for mutated SDCs from both highly and (particularly) moderately carboxin-resistant SDCs of U. maydis, markedly lowering the resistance level, i.e., the degree of resistance. Thus, in addition to the oxathiins, specific structural groups of thiophene carboxamides can also alleviate or reverse the effect of carboxin-selected mutation with reference to inhibition of the SDC. Of important significance was the finding that molecular selectivity for mutated, carboxin-resistant SDCs can be influenced by replacement of an oxathiin by a thiophene heterocyclic ring as well as by the substitutive group on the amide nitrogen, permitting different categories of mutant types and even mutants within a single category to be distinguished from one another. With all the structural combinations available, it appears quite possible, in terms of inhibition, to overcome any type of mutation in a fungal SDC which arises through selection by carboxin or other carboxamide compounds. A reasonable correlation generally exists between inhibition by thiophene carboxamides of the SDC and sporidial growth of wild-type and carboxin-resistant strains of U. maydis. A permeability barrier to 4′-substituted analogs of (I) was encountered in the wild-type strain but not mutant strains. Excellent protectant activity against bean rust (Uromyces phaseoli) was obtained with the 3′-nhexyl, 3′-nhexyloxy, and 4′-phenoxy analogs of (I).     

Structure-activity relationships in fungitoxicants related to triforine and chloraniformethan. Part IV: Evaluation of the predictive power of the Hansch analysis by the preparation and testing of further chloraniformethan analogues

Seven chloraniformethan analogues, which were predicted, on the basis of the quantitative Hansch analysis performed previously, to be as active as the parent compound against barley powdery mildew (Erysiphe graminis), were prepared. Their activity as leaf sprays against E. graminis was much lower than that calculated using the regression equations, indicating that the Hansch analysis is not a suitable method for predicting fungitoxicity in this chloraniformethan series of compounds.