Synthesis and structure-activity study of fungicidal anilinopyrimidines leading to mepanipyrim (KIF-3535) as an anti-Botrytis agent

A series of 2-anilinopyrimidines was prepared and their fungicidal activities against Botrytis cinerea Pers were examined. The activity fell sharply with any substitution on the anilinobenzene ring. Substituents at the 5-position of the pyrimidine ring greatly reduced the activity. Substituents such as chloro, methoxy, methylamino, methyl or 1-propynyl were well tolerated at the 4- and 6-positions of the pyrimidine ring. Among these substituents, the combination of methyl and 1-propynyl groups was the most favourable. 2-Anilino-4-methyl-6-(1-propynyl)pyrimidine (KIF-3535), which showed excellent activity and no significant phytotoxicity, was finally selected for development and has been given the common name mepanipyrim.     

Fenbendazole. I. Structure-activity relationships

Substitution of alkyl benzimidazol-2-ylcarbamates by phenoxy- or phenylthio-groups in the 5-position results in an increase in anthelmintic activity. The biological spectrum is altered by substitution of the phenyl ring. A sulphonic ester substituent in the 5-position of the benzimidazole nucleus also increases anthelmintic activity.     

Synthesis and herbicidal activity of substituted tetrahydronaphthalenes: I

This paper reports the synthesis and the biological activity of substituted 6-alkyl-1,2,3,4-tetrahydro-1,1-dimethylnaphthalenes in which the substituents at the 5- and/or 7-position are varied with a multitide of functional groups. These compounds exhibited pre-emergent herbicidal activity which was a function of the electron-withdrawing ability and the size of the groups substituted at the 5- and/or 7-position. Nitro and/or nitrile groups at these positions tended to optimize activity.     

Dimethoxypyrimidines as Novel Herbicides. Part 1. Synthesis and Herbicidal Activity of Dimethoxyphenoxyphenoxypyrimidines and Analogues

A number of 6-(4-phenoxyphenoxy)pyrimidines and triazines were synthesized and their herbicidal activity was measured. Compounds with the methoxy groups at the 2- and 4-positions on the pyrimidine and triazine rings exhibited high herbicidal activity. Introduction of a substituent into the 5-position of the pyrimidine ring diminished the activity. In the phenoxyphenoxy substructure at the 6-position, the central ether bond can be replaced by a methylene group without loss of activity. The optimum substituent on the terminal phenyl ring was 3-trifluoromethyl. The compounds showed a strong Hill reaction inhibition, but unfortunately showed poor selectivity between weeds and crops.     

New 2-phenyl-4,5,6,7-tetrahydro-2H-indazole derivatives as paddy field herbicides

A series of 3-chloro-2-(4-chloro-2-fluorophenyl)-4,5,6,7-tetrahydro-2H-indazole derivatives containing various substituted isoxazolinylmethoxy groups at the 5-position of the benzene ring were synthesized and their herbicidal activities assessed under greenhouse and flooded paddy conditions. Among them, compounds having a phenyl or cyano substituent at the 3-position of the 5-methyl-isoxazolin-5-yl structure demonstrated good rice selectivity and potent herbicidal activity against annual weeds at 16-63 g AI ha(-1) under greenhouse conditions. Field trials indicated that these two compounds controlled a wide range of annual weeds rapidly with a good tolerance on transplanted rice seedlings by pre-emergence application. They showed a low mammalian and environmental toxicity in various toxicological tests.     

Juvenile hormonal activity of mono- and polyenehomobenzenes in Drosophila virilis, Spodoptera frugiperda and Araschnia levana

A series of mono- and polyenehomobenzenes was synthesised by a highly regioselective palladium-catalysed allylic alkylation of substituted and unsubstituted benzylic Grignard reagents employing catalytic amounts of catalyst and tested for juvenile hormone activity on the fruit fly Drosophila virilis Sturtevant (Diptera: Drosophilidae), on an important agricultural pest species, the fall armyworm Spodoptera frugiperda JE Smith (Lepidoptera: Noctuidae), and on the map butterfly Araschnia levana L. (Lepidoptera: Nymphalidae). In D. virilis only polyenehomobenzenes with a geranyl chain and a methyl, methoxy or isopropyl group at the para position of the aromatic ring displayed significant juvenile hormonal activity at low doses. A monoenehomobenzene and polyenehomobenzenes with longer allylic chains or without a substituted aromatic ring were not active. In S. frugiperda and in A. levana, a mono-, a di- and a tetraene displayed juvenile hormonal activity. In the lepidopteran species, a trend for the necessity of a substitution at position 4 of the phenyl group for high juvenile hormonal activity was also found.     

The chemistry and biological activity of a new class of azole fungicides: 1-amino-1,2,4-triazoles

The fungicidal activity of a novel class of triazole compounds in which the 1-position of the azole nucleus is bonded to a nitrogen atom was investigated. Such 1-amino-1,2,4-triazoles are amenable to great structural variation which allows the elucidation of the requirements for biological activity. As in most other triazole fungicides, the basic structural requirement for activity is a two-atom bridge connecting the azole nucleus to a hydrophobic group, typically an aromatic ring. The synthesis and optimization of fungicidal activity of this class of triazole fungicide are discussed.     

Fungicidal activity of substituted quinoxalines

Twenty substituted quinoxalines based on the structure of 6 (or 7)-methyl-3-phenyl-1, 2-dihydroquinoxalin-2-one, a fungicidally active photodegradation product of quinomethionate, were synthesised. Eleven of these compounds had ED₅₀ values, as protectant sprays against Podosphaera leucotricha, of 0.1 mmol or less; these compounds had an aromatic substituent at the 3-position of the quinoxaline ring. They were less active as protectant leaf dips against Erysiphe graminis f. sp. hordei than against Podosphaera leucotricha; none showed any systemic activity as a soil-applied treatment against Podosphaera leucotricha. One compound was more active than quinomethionate as an eradicant spray. In spore germination tests on fungi from different taxonomic groups, the quinoxaline derivatives were active against only one basidiomycete (Uromyces fabae), whereas quinomethionate showed a broad spectrum of activity. The possible significance of this difference in spectrum of activity with respect to the mode of action is discussed.     

The pyrethrins and related compounds. Part XXVIII: Alkenyl- and alkynyl-substituted benzyl esters

Over 100 benzyl esters of pyrethroidal acids were synthesised and tested for insecticidal activity to establish detailed structure–activity relationships in compounds with side-chains similar to those in the natural pyrethrins. Alkenyl, and corresponding alkynyl, side-chains were effective, both at the 3- and 4-positions, as were side-chains with extended substitution in either E or Z forms. A cyano group at the α-position increases activity if the side-chain is at C-3, but lowers it drastically if the substituent is at C-4. Similarly, methyl groups at C-2 and/or C-6 may increase activity whether the unsaturated side-chain is at C-3 or C-4, but only in the absence of an α-cyano group.     

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.     

Insecticidal activity of the pyrethrins and related compounds. Part XIIIa: Comparison of the effects of a-substituents in different esters

The insecticidal activities of esters from a series of alcohols with four different groups (H, -CH₃, -C?CH and -C?N) in the α-position, and containing different A-rings or bridging groups, were evaluated. The results show a complex interaction between these two parts of the molecule; the strongest enhancement of activity by some α-substituents was found in 3-phenoxybenzyl esters, while other systems responded weakly or even negatively to the substitution.     

Synthesis,structure and herbicidal activity of pyrazol-4-yl alkyl ketone derivatives

Novel 5-amino-1-phenylpyrazol-4-yl alkyl ketones were synthesised and their herbicidal properties evaluated. Active compounds in the series induced accumulation of protoporphyrin IX in etiolated cucumber cotyledons and caused light-dependent herbicidal effects in 21-day-old cucumber plants. Structural features of the pyrazoles that contributed to herbicidal potency were found to be a high degree of halogen substitution in the 1-phenyl ring, no substitution in the pyrazole 3-position, and an ethyl group as the alkyl component of the ketone. The structure of 1-[5-amino-1-(2,4,6-trichlorophenyl)pyrazol-4-yl]-2-methylpropan-1-one was determined by X-ray crystallography.     

Effect of substituents at the 5-position of the pyridine ring of imidacloprid on insecticidal activity against Periplaneta americana

The insecticidal activities of imidacloprid derivatives with a wide range of substituents at the 5-position on the pyridine ring against American cockroaches, Periplaneta americana (L.), were measured by injection with and without synergists propyl 2-propynyl phenylphosphonate and piperonyl butoxide. The log(1/MLD) value (MLD = minimal lethal dose in mol) without synergists was 7.96 for the methyl derivative, and the values were lower for other derivatives. Synergists enhanced the potencies of all the compounds tested. Considering these compounds and those with other substituents at this position, the region for maximum activity was predicted to be in the conjunction of the pyridyl 6-chlorine atom with a lipophilic small group in the 5-position.     

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

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

New melanin biosynthesis inhibitors and their structural similarities

Relationships between their activities as blast control agents, and their abilities to inhibit mycelial melanisation on a nutrient agar, are described for 103 substituted benzothiazol-2(3H)-ones, benzoxazol-2(3H)-ones, indolin-2-ones, quinolin-2(1H)-ones, 1,2,3,4-tetrahydroquinolin-2-ones, benzo-1,4-thiazin-3(2H)-ones and benz-1,4-oxazin-3(2H)-ones, and some corresponding thiones. Several compounds in the respective series had a high protective activity and an antimelanisation activity against the blast fungus Pyricularia oryzae; furthermore, there was a good correlation in both of these activities, indicating that these compounds belong to the group of melanin biosynthesis inhibitors. Structural similarities of these compounds can be identified as follows: (a) having a benzo-bicyclic ring system; (b) containing a nitrogen atom in one ring at a position alpha to the benzene ring system; and (c) substitution, at the ring nitrogen atom, at the peri position in the aromatic ring relative to the nitrogen atom, and at the position alpha to the nitrogen atom in the ring system, with a double bond such as in carbonyl and thiocarbonyl groups. Among the compounds that have been proposed as melanin biosynthesis inhibitors, the chemical structures of tricyclazole, pyroquilon, 4,5-dihydro-4-methyltetrazolo[1,5-a]quinazolin-5-one (PP-389), [1,2,4]-triazolo[4,3-a]quinoline and 1-methylquinolin-2(1H)-one exhibit the structural similarities described above; however, 4,5,6,7-tetrachlorophthalide, 2,3,4,5,6-pentachlorobenzyl alcohol and N-substituted-2,3,4,5-tetrachloro-6-(hydroxymethyl)benzamides do not have such similarities in their chemical structures.     

Chemical structure-fungicidal activity relationships in substituted morpholines

By the N-substitution of morpholine with alkyl or cycloalkyl groups containing 12 to 13 carbon atoms, compounds were obtained with good fungicidal activity, in particular, against powdery mildew in barley. An increase in activity was achieved when the carbon atoms in the heterocyclic ring bore one or two methyl groups, the 2,6-combination being preferred. In the case of sterically different substances, no difference in activity was observed between the cis- and trans-forms. Substituted arylalkyl amines, in which the aromatic ring and the alkylene chain were substituted appropriately, showed very good activity against powdery mildew in wheat and barley, as well as against cereal rust fungi. Steric conditions also play an important role with this type of molecule, as has been proved by detailed investigations on isomers with different configurations in the morpholine moiety, in the alkylene intermediate chain, and in the carbocycle.     

含4-正庚/正辛氧基苯基杂环化合物的设计、合成及生物活性

通过研究苯甲脒类抑制剂与酮醇酸还原异构酶(KARI)对接的结合模式,设计合成了一系列含正庚氧基及正辛氧基苯基的杂环化合物。用核磁共振氢谱、红外光谱、质谱及元素分析对26个目标产物(其中22个是新化合物)的结构进行了表征和确认。初步生物活性测试结果表明,目标化合物大多具有不同程度的水稻KARI酶抑制活性和除草活性,其中化合物 9a和9b 在200 μg/mL浓度下对KARI酶的抑制率分别为65.7%和71.1%,在100 μg/mL浓度下对双子叶植物油菜Brassica campestris的抑制率分别达78.6%和89.0%。     

The pyrethrins and related compounds. Part XXIX: Haloallylbenzyl esters

Synthesis and bioassay of a series of esters based on pyrethroidal acids established that the activity of halosubstituted allylbenzyl esters depends on the position and stereochemistry of substitution in the allyl side-chain, on the substitution pattern on benzyl, on the esterifying acid, and, to a lesser extent, on the nature of the halogen substituent itself. The most powerful combination of the first four parameters for activity against houseflies is in (Z)-3-haloallylbenzyl esters of the (1R)-cis 3-(2,2-dibromovinyl) acid. Other combinations have moderate to low activity. Some aspects of the variation conform to previously recognised patterns, others define more precisely the requirements for the side-chain to confer activity. The pattern of response of activity to cyano-substitution at the α-position, noted earlier, persists in the current compounds, and is here analysed quantitatively.     

Synthesis and fungicidal activity of phenanthridinotriazines: A structure–activity relationship study

A series of analogous tetracyclic 1, 12b-dihydro-4H-1,2,4-triazino[4,3-f] phenanthridines and 4H,12bH-1,2,5-oxadiazino[5,6-f]phenanthridines was prepared and tested for control of Erysiphe graminis f. sp. tritici (the causal agent of powdery mildew in wheat). Several analogs showed exceptional activity at doses as low as 6.25 mg litre^?1 with substituted analogs VII, X , and XIV being the most potent. Singly substituted tetrahydrotriazinyl or oxadiazenyl rings with lipophilic aromatic components appeared to be the key requirements for optimal powdery mildew control. Substitution of the heterocyclic ring with multiple groups attenuated activity.     

Prediction of the binding mode of imidacloprid and related compounds to house-fly head acetylcholine receptors using three-dimensional QSAR analysis

The binding activity of imidacloprid and related compounds to nicotinic acetylcholine receptors (nAChR) of house flies was measured by use of radioactive α-bungarotoxin as a ligand. Variations in the activity were examined three-dimensionally using comparative molecular field analysis (CoMFA). The CoMFA results suggest that one conformer among the four stable ones is active and provide support for one of the proposed binding models for this class of compound, in which the nitrogen atom of the pyridine ring and the nitrogen atom at the 1-position of the imidazolidine ring interact with the hydrogen-donating and electron-rich sites of nAChR, respectively. The CoMFA field map showed that the nitroimino moiety and a portion of the imidazolidine ring were mainly surrounded by a sterically and electrostatically sensitive region of nAChR. © 1998 Society of Chemical Industry