Novel acetylcholinesterase inhibitors: Synthesis and structure–activity relationships of phthalimide alkyloxyphenyl N,N-dimethylcarbamate derivatives

Based on the multiple binding sites of acetylcholinesterase (AChE), a series of AChE inhibitors: phthalimide alkyloxyphenyl N,N-dimethylcarbamate were designed and synthesized. AChE inhibitory activity and structure–activity relationship of the compounds were researched also. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different alkyloxy chain length and position between phthalimide and phenyl N,N-dimethylcarbamate (PDM). The biological properties of the series were investigated by considering the activity on isolated enzyme. Some of the newly synthesized derivatives, when tested on isolated AChE from head of housefly (Musca domestica), were more active than PDM. The compounds J1, J2 and K1–K8 demonstrated higher inhibitory activity (5- to 404-fold) for AChE than that of PDM. In particular, compound K1 displayed the best AChE inhibition (404-fold higher than PDM), which suggested that phthalimide group of K1 strongly bound at the residues lining the gorge while phenyl N,N-dimethylcarbamate bound at the catalytic site.     

Synthesis and fungicidal activities of positional isomers of the N-thienylcarboxamide

To investigate the effects of bioisosteric replacement of the phenyl group with the thienyl group, N-phenylcarboxamide and three regioisomers of N-(substituted-thienyl)carboxamide were synthesized. The inhibitory activity on the succinate dehydrogenase prepared from the gray mold Botrytis cinerea as well as the fungicidal activity against B. cinerea were evaluated. Two isomers, N-(2-substituted-3-thienyl)carboxamide and N-(4-substituted-3-thienyl)carboxamide exhibited the same level of activity as the phenyl derivative, whereas N-(3-substituted-2-thienyl)carboxamide exhibited lower activity than the phenyl derivative, suggesting that the 2-substituted-3-thienyl and 4-substituted-3-thienyl groups functioned as bioisosteres of the phenyl group in N-phenylcarboxamide, but the other did not.     

β-Oxidation of certain growth regulators by plant tissues

The growth-regulating activity and metabolism, in pea and wheat tissues, of y-(chloro-phenoxy)-, y-(2,4-dichlorophenoxy)- and y-(N, N-diniethylthiocarbamoylthio)-substituted butyric, β-hydroxy-butyric, crotonic and vinylacetic acids have been investigated. With the exception of y-(2,4-dichlorophenoxy) vinylacetic acid in pea tissue, members of the two phenoxy series were degraded to the corresponding phenoxyacetic acid. Although members of the 2,4-dichlorophenoxy series were less easily metabolised, both series exhibited similar activity. Other than with the y-phenoxyvinylacetic acids, there were no appreciable differences in metabolism or growth-regulating activity between members within a series. No evidence for the metabolism of y-(2,4-dichlorophenoxy)vinylacetic acid in pea tissue was found and this acid was also less active in the pea tests. Members of the N, N-dimethyl-thiocarbamoylthio series of acids, however, were less regular in their metabolic and growth-regulating patterns. The substituted crotonic acid was inactive and unstable whilst pea tissue was found to metabolise the substituted acetic acid to inactive N-methylcarbamoylthioacetic acid. The results with all active acids fit the accepted theory of metabolism by β-oxidation.     

Design, synthesis, insecticidal activity and structure-activity relationship of 3,3-dichloro-2-propenyloxy-containing phthalic acid diamide structures

BACKGROUND: Phthalic acid diamide derivatives are among the most important classes of synthetic insecticides. In this study, a 3,3‐dichloro‐2‐propenyloxy group, the essential active group of pyridalyl derivatives, was incorporated into phthalic acid diamide derivatives with the aim of combining the active groups to generate more potent insecticides. RESULTS: Thirty‐one new phthalic acid diamides were obtained, and these were characterised by ¹H and ¹³C NMR. The structure of N²‐[1,1‐dimethyl‐2‐(methoxy)ethyl]‐3‐iodo‐N¹‐[4‐(3,3‐dichloro‐2‐propenyloxy)‐3‐(trifluoromethyl)phenyl]‐1,2‐benzenedicarboxamide was determined by X‐ray diffraction crystallography. The insecticidal activities of the compounds against Plutella xylostella were evaluated. The title compounds exhibited excellent larvicidal activities against P. xylostella. Structure‐activity relationships revealed that varying the combination of aliphatic amide and aromatic amide moieties, or the nature and position of substituent Y on the aniline ring, could aid the design of structures with superior performance. CONCLUSION: A series of novel phthalic acid diamides containing a 3,3‐dichloro‐2‐propenyloxy group at the 4‐position of the aniline ring were designed and synthesised. Structure‐activity relationships with the parent structure provided information that could direct further investigation on structure modification. Copyright © 2012 Society of Chemical Industry     

Photolysis of dichlofluanid

Dichlofluanid was found to be degraded by ultraviolet light in methanol, benzene and acetone solution. The products from acetone solution included N,N-dimethyl-N′-phenylsulphamide, phenyl isocyanate, phenyl isothiocyanate and dimethylamidosulphonyl chloride. G.c.-m.s. studies further indicated the presence of bis(dichlorofluoromethyl) disulphide, 1-(dichlorofluoromethylthio)propan-2-one and 1-(dichlorofluoromethylsulphonyl)propan-2-one. In-vitro tests against Botrytis cinerea showed that irradiation decreased the activity of dichlofluanid and that synergism did not occur.     

Fungicidal activity and chemical constitution: XVII.—Activity of various 4-(1-substituted n-alkyl)-2,6-dinitrophenols and esters against apple powdery mildew

Members of series of 4-(cyclobutylalkyl, cyclohexylalkyl and benzylalkyl)-2,6-dinitrophenols were tested in a glasshouse against apple powdery mildew caused by Podosphaera leucotricha. Three series involving a cyclohexyl substituent separated from the phenolic nucleus by one, two or three methylene groups were of the same order of activity, but replacement of this substituent by a phenyl group in one case, resulted in a marked decrease in activity. Of a number of esters tested, none was significantly more active than the corresponding phenol.     

新型含吡唑杂环邻氨基苯甲酰胺类化合物的合成与杀螨活性

以氯虫苯甲酰胺和氟虫腈的结构为基础,通过活性亚结构拼接的方法,设计合成了24个新型含吡唑杂环邻氨基苯甲酰胺类化合物,其结构经1H NM R、IR及APCI-M S表征。初步生物活性测试结果表明:化合物5-溴-N-[4-氯-2-甲基-6-(甲氨基甲酰基)苯基]-1-1-[2,6-二氯-4-(三氟甲基)苯基]-4-三氟甲基亚磺酰基-1H-吡唑-3-甲酰胺(5k)和5-溴-N-[4-溴-2-甲基-6-(甲氨基甲酰基)苯基]-1-[2,6-二氯-4-(三氟甲基)苯基]-4-三氟甲基亚磺酰基-1H-吡唑-3-甲酰胺(5l)在500 mg/L下对朱砂叶螨Tetranychus cinnabarinus的致死率为100%,但在100 mg/L下其致死率则分别降至30%和50%。所得结果可为邻氨基苯甲酰胺类化合物构效关系研究提供参考。     

Synthesis of benzylaminopyrimidines and their fungicidal activities against wheat brown rust and barley powdery mildew

Members of a new class of fungicide containing benzylaminopyrimidine as a core structure were synthesized and their fungicidal potencies against wheat brown rust, Puccinia recondita, and barley powdery mildew, Erysiphe graminis, were assessed. Among these fungicides, N-(fluoroalkoxy or fluorophenoxybenzyl)-4-pyrimidinamines showed notable preventive activities. The potency of the new pyrimidines was increased when a difluoromethoxy or tetrafluorophenoxy group was introduced at the 4- or 3-position of the phenyl moiety and a methyl or ethyl group was introduced at the benzyl position. Structure–activity relationships are discussed. © 1998 Society of Chemical Industry     

Synthesis and insecticidal activity of novel 1,3,4-oxadiazolin-5-one and pyrazolin-5-one derivatives

A series of novel 2-(2,4,6-trisubstituted phenyl)-1,3,4-oxadiazolin-5-one derivatives and 3-(2,4,6-trichlorophenyl)pyrazolin-5-one derivatives were synthesized and evaluated for insecticidal activity. It was found that a moderately bulky alkyl group, such as a tert-butyl group, on the heterocyclic ring, and a trifluoromethyl group on the benzene ring were optimal substituents on the molecule. The oxygen atom in the oxadiazoline ring was essential for insecticidal activity. Of the compounds assayed, 4-tert-butyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-5-one gave the highest activity against Nephtotettix cincticeps, with an LC₅₀ value of 0.51 mg litre⁻¹. © 1999 Society of Chemical Industry     

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.     

Antimicrobial activity of some N-(arylalkyl)maleimides

A series of N-(arylalkyl)maleimides was prepared for the reaction of maleic anhydride and N-(arylalkyl) amines, and their antimicrobial activities were examined. All compounds exhibited antibacterial activity against gram-positive bacteria such as Bacillus subtilis and Staphylococcus aureus. Almost all compounds exhibited antibacterial activity against the gram-negative bacterium, Escherichia coli, but were inactive against Pseudomonas aeruginosa. Activities against gram-positive bacteria were independent of the nature of the substituent on the benzene ring or the length of alkyl group, but that against gram-negative bacteria was influenced by these parameters. All N-(arylalkyl)maleimides showed activity against yeasts and mycelial fungi.     

The antifungal activity of some sulphonyl derivatives of isoxazole,pyrazole, thiazole and thiophene

Fifty-three heterocyclic sulphonyl derivatives including eight sulphonamides, three sulphonyl azides, nine sulphonohydrazides and twenty sulphonohydrazones of substituted thiophenes, and a smaller range of analogous isoxazoles pryazoles and thiazoles, were tested as potential fungicides in a simple screening procedure against Mucor mucedo, Septoria nodorum, Trichoderma viride, Chaetomium globosum and Aspergillus niger. Several thiophene-2-sulphonyl based compounds exhibited a high level of antifungal activity at 100 mg litre^?1 against the five test species, especially the mono-halogen-substituted sulphonamides and sulphonohydrazines, in which a single chlorine or bromine atom was substituted in the para position of an attached phenyl ring. The most active compound, against all five species of fungus was N-(4-chlorophenyl)-N-(trichloromethylthio) thiophene-2-sulphonamide which had average MIC₅₀ and MIC₁₀₀ values of 86 and 180 μmol respectively. (MIC₅₀ and MIC₁₀₀ values are, respectively, the concentrations required to inhibit fungal growth by 50% and to inhibit it totally.) In general, the isoxazole analogues of the thiophene-2-sulphonyl compounds exhibited a much lower fungitoxic activity, whilst the pyrazole and thiazole based compounds had little or no activity. Compared with the other results, the considerable activity shown by 4-[2′-(3,4-dichlorobenzylidene)hydrazinosulphonyl]thiophene-2-carboxylic acid was unexpected.     

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.     

Synthesis and insecticidal activity of lipophilic amides. Part 1: Introductory survey,and discovery of an active synthetic compound

A group of naturally occurring isobutylamides and related compounds exhibit a range of biological properties including activity against insects. Their potential as a starting point for developing new insecticides, needed to control pests resistant to other classes of insecticides, is discussed, following an extensive survey of known structures and activities. Few of the known compounds were sufficiently active and well characterised to point to sound structure-activity relationships, so synthetic analogues were examined. One of these [(2E,4E)-N-(2-methylpropyl)-6-phenylhexa-2,4-dienamide] was sufficiently active, and prompted the investigations reported here and in subsequent papers in the series. Analogues of this compound designed to establish areas where structural variation is possible are also described.     

Synthesis and antifungal activity of imidazole-1-carboxylates

A series of imidazole-1-carboxylates was prepared by reacting various alcohols with trichloromethyl chloroformate and imidazole or N,N'-carbonyl-diimidazole. They were tested for fungitoxic activity in vitro against two phytopathogenic fungi, Botrytis cinerea (grey mould) and Gibberella fujikuroi, and for preventive efficacy against grey mould on cucumber leaves. 1-(4-Substituted phenoxymethyl)-2,2-dimethylpropylimidazole-1-carboxylates showed excellent in-vitro activity against B. cinerea, and moderate activity against G. fujikuroi, and some of them also effectively controlled grey mould in vivo. A 1H-1,2,4-triazole derivative corresponding to an imidazole derivative did not have any activity, while a thiocarboxylate corresponding to an imidazole carboxylate showed excellent activity against both B. cinerea and G. fujikuroi.     

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.     

Insecticidal activity of N,N-diethyl-, N,N-dipropyl-, N,n-di-isopropyl-, and n,n-di-isobutylalkanamides against mosquito larvae

N,N-Diethyl-, N,N-dipropyl-, N,N-di-isopropyl, and N,N-di-isobutylalkanamides in which the acyl moiety ranged from C₈ to C₂₁ were synthesised, and their larvicidal activity was determined against the first-instar larvae of the southern house mosquito Culex quinquefasciatus Say. The four homologous series of amides generally showed an increase in their larvicidal activity as the carbon number in the acyl moiety of the amides increased, until the activity reached a maximum. Subsequently, an increment of carbon number resulted in declining activity in the higher homologues, until the activity disappeared. N,N-Diethyltetradecanamide, N,N-dipropylundecanamide, N,N-di-isopropylundecanamide, and N,N-di-isobutlynonanamide or -dodecanamide were the most active compounds in their respective homologous series of amides; however, they were less active than their analogous N,N-dimethylalkanamides previously studied.     

Synthesis and biological evaluation of [1-(1H-1,2,4-triazol-1-yl)alkyl]-1-silacyclopentanes

A series of 1-aryl-1-(1H-1,2,4-triazol-1-yl)alkyl-1-silacyclopentanes has been synthesized by four-step reactions starting from 1-chloroalkyltrichlorosilane and tested for fungicidal activities in vitro for ten fungi and in vivo for four fungi occurring in rice, cucumber, tomato etc. Biological activities of the title compounds are strongly dependent upon the p-substituent on the phenyl group in the following order: F>Cl>Ph>OEt>H. Especially, 1-p-fluorophenyl-1-[1-(1H-1,2,4-triazol-1-yl)alkyl]-1-silacyclopentanes (alkyl=methyl or ethyl) showed significant fungicidal activity with a broad spectrum comparable to flusilazole in in-vivo assay. © 1998 SCI.     

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.     

Structure—activity relationships of pyridylcarbamates active against both benzimidazole-sensitive and -resistant isolates of Botrytis cinerea

A series of pyridylcarbamates showed high potency against cucumber gray mould (Botrytis cinerea Pers.). The most potent compound, propargyl-N-(6-ethyl-5-iodo-2-pyridyl)carbamate was effective against an isolate sensitive to benzimidazole and dicarboximide fungicides as well as against an isolate resistant to both types of compound. QSAR analyses and molecular modelling studies were carried out to investigate the structural requirements for highly active compounds and the structural feature of the binding site of each strain. Significantly different QSAR equations were obtained only for substituents at the 6-position of the pyridine ring. An ethyl-sized pocket or an ethyl terminal recognition was suggested in the case of the sensitive or resistant isolate respectively. These results could explain the phenomenon of negatively correlated cross-resistance between benzimidazoles and N-phenylcarbamate fungicides. Substituent effects at the 5- or 2-position were governed by steric factors. Substituent effects at the 3-position were explained by steric hindrance or by conformational effects. The propargyl-substituted compound above was the most desirable one from the viewpoint of QSAR.