Synthesis and herbicidal activity of 3-substituted toxoflavin analogs

We investigated the synthesis and herbicidal activity of 23 toxoflavin analogs, 1a–w, in which aromatic rings (R) were introduced into the C-3 position. In paddy field conditions, 1k (R=2-CF₃–C₆H₄) and 1w (R=2-thienyl) showed excellent herbicidal activity. Under upland field conditions, we found that toxoflavin analogs 1a (R=C₆H₅), 1n (R=2-CH₃O–C₆H₄), and 1p (R=4-CH₃O–C₆H₄) exhibited wide herbicidal spectrum against Echinochloa crus-galli (L) var. crus-galli (ECHCG), Chenopodium album, and Amaranthus viridis (AMAVI). The analog with the 2-fluoro group on benzene ring 1b also showed high herbicidal activity against both ECHCG and AMAVI.     

Synthesis and characterization of a group of dihydropyrimido-benzimidazole photosystem II herbicides

A group of 28 dihydropyrimido-benzimidazole analogs and derivatives was tested for herbicidal activities. The 1:1 mixture of 7-fluoro- and 8-fluorodihydropyrimido-benzimidazole had the greatest biological activity. Activity is increased by methylation of nitrogen 2. None of the active compounds was inhibitory to nonphotosynthetic tissue-culture cells in vitro. The I₅₀ of inhibition of growth of green duckweed plants and that of in vitro photosynthesis activity matched the I₅₀ of inhibition of photosystem II activity. Fluorescence analyses of photosystem II activity indicated inhibition at the same step as did many triazine, phenylurea, pyridazinone, and uracil herbicides. As the compounds showed insufficient activity on recently evolved triazine-resistant weed biotypes, their further development was terminated, despite their novel chemistry.     

Environmental degradation of the insect growth regulator methoprene: V. Metabolism by houseflies and mosquitoes

The metabolism of methoprene (I, isopropyl (2E,4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate, trademark Altosid) was investigated in larval mosquitoes and houseflies. The most abundant primary metabolite in third- and fourth-instar Aedes and fourth-instar Culex larvae was the hydroxy ester while the hydroxy acid predominated in third-instar Musca larvae. Biological isomerization of the double bond at C-2 in I (i.e., conversion of (E) to (Z)) was an effective mode of insect detoxication, but these dipterans apparently cannot isomerize the (2Z) isomer of I to methoprene. In general, piperonyl butoxide and triorthocresyl phosphate slightly increased the morphogenetic activity of I in these insects.     

米尔贝霉素类似物的合成及杀螨杀蚜活性

为寻找高活性的米尔贝霉素衍生物,以伊维菌素为原料,经脱糖、羟基保护、氧化、还原胺化、脱保护等将其转变为13-氨基米尔贝霉素类似物,通过三组分反应设计合成了一系列米尔贝霉素磺酰脒类化合物(7a~7i),并初步测定了其对朱砂叶螨Tetranychus cinnabarinus和豆蚜Aphis craccivora的室内活性。结果表明:各衍生物对朱砂叶螨和豆蚜均有较好的触杀活性,其中7f、7h和7i对朱砂叶螨24 h的LC50值分别为1.04×10–2、9.60×10–4和1.44×10–2 mg/L;7i对豆蚜24 h的LC50值为7.81 mg/L。米尔贝霉素13位氨基上磺酰化的结构修饰有助于提高米尔贝霉素类化合物的杀螨、杀蚜活性。     

Insecticidal 3-benzamido-N-phenylbenzamides specifically bind with high affinity to a novel allosteric site in housefly GABA receptors

γ-Aminobutyric acid (GABA) receptors (GABARs) are an important target for existing insecticides such as fiproles. These insecticides act as noncompetitive antagonists (channel blockers) for insect GABARs by binding to a site within the intrinsic channel of the GABAR. Recently, a novel class of insecticides, 3-benzamido-N-phenylbenzamides (BPBs), was shown to inhibit GABARs by binding to a site distinct from the site for fiproles. We examined the binding site of BPBs in the adult housefly by means of radioligand-binding and electrophysiological experiments. 3-Benzamido-N-(2,6-dimethyl-4-perfluoroisopropylphenyl)-2-fluorobenzamide (BPB 1) (the N-demethyl BPB) was a partial, but potent, inhibitor of [³H]4′-ethynyl-4-n-propylbicycloorthobenzoate (GABA channel blocker) binding to housefly head membranes, whereas the 3-(N-methyl)benzamido congener (the N-methyl BPB) had low or little activity. A total of 15 BPB analogs were tested for their abilities to inhibit [³H]BPB 1 binding to the head membranes. The N-demethyl analogs, known to be highly effective insecticides, potently inhibited the [³H]BPB 1 binding, but the N-methyl analogs did not even though they, too, are considered highly effective. [³H]BPB 1 equally bound to the head membranes from wild-type and dieldrin-resistant (rdl mutant) houseflies. GABA allosterically inhibited [³H]BPB 1 binding. By contrast, channel blocker-type antagonists enhanced [³H]BPB 1 binding to housefly head membranes by increasing the affinity of BPB 1. Antiparasitic macrolides, such as ivermectin B_1a, were potent inhibitors of [³H]BPB 1 binding. BPB 1 inhibited GABA-induced currents in housefly GABARs expressed in Xenopus oocytes, whereas it failed to inhibit l-glutamate-induced currents in inhibitory l-glutamate receptors. Overall, these findings indicate that BPBs act at a novel allosteric site that is different from the site for channel blocker-type antagonists and that is probably overlapped with the site for macrolides in insect GABARs.     

Albumin and cytochrome P450 binding characteristics of juvenile hormone and its analogs

Binding data were gathered for the cecropia juvenile hormone (methyl(E, E cis)-10,11-epoxy-7-ethyl-3,11-dimethyl-2,6-tridecadienoate) and two of its analogs {isopropyl(2E, 4E)-11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate; (E)-4-[(6,7-epoxy-3,7-dimethyl-2-nonenyl)-oxyl]-1,2-(methylenedioxy)benzene} with bovine serum albumin and rat hepatic microsomal cytochrome P₄₅₀. The proteins were found to bind the juvenile hormone and juvenile hormone analogs with affinity constants ranging from 10⁵ to 10⁶M^?1. Thermodynamic calculations suggest that the binding of all three compounds is electrostatic in nature and that the size of the ether and ester substituents can greatly influence the binding to proteins. The juvenile hormone and its analogs all formed spectrally apparent Type I complexes with oxidized cytochrome P₄₅₀; one of the juvenile hormone analogs formed a spectrally observable product adduct with reduced cytochrome P₄₅₀. The product complex may contribute many of the hormonal effects observed for this compound.     

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.     

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.     

Isolation of a phytotoxic isocoumarin from Diaporthe eres‐infected Hedera helix (English ivy) and synthesis of its phytotoxic analogs

BACKGROUND

The fungus Diaporthe eres was isolated from a fungal pathogen‐infected leaf of Hedera helix (English ivy) exhibiting necrosis. It is hypothesized that the causative fungus produces phytotoxins as evidenced by necrotic lesions on the leaves.

RESULTS

The fungus was isolated and grown in Czapek Dox broth culture medium and potato dextrose broth culture medium and identified as Diaporthe eres. The ethyl acetate extracts of the culture broths were phytotoxic to lettuce (Lactuca sativa) and bentgrass (Agrostis stolonifera). 3,4‐Dihydro‐8‐hydroxy‐3,5‐dimethylisocoumarin ( 1 ) and tyrosol ( 2 ) were isolated and identified as the phytotoxic constituents. Six analogs of 3,4‐dihydro‐isocoumarin were synthesized and shown to be phytotoxic. The synthesized 3,4‐dihydro‐8‐hydroxy‐3,7‐dimethylisocoumarin and 3,4‐dihydro‐8‐hydroxy‐3,3,7‐trimethylisocoumarin were two‐ to three‐fold more phytotoxic than the naturally occurring 1 in a Lemna paucicostata growth bioassay.

CONCLUSION

Synthesis and herbicidal activities of the several new analogs of 1 are reported for the first time. These promising molecules should be used as templates for synthesis and testing of more analogs. © 2017 Society of Chemical Industry     

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 ( E_s ). 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     

Antifungal mode of action of triforine

Rapidly growing mycelia of Aspergillus fumigatus treated with 10 μg/ml triforine (N,N′-bis-(1-formamido-2,2,2-trichloroethyl)-piperazine) showed little or no inhibition in dry weight increase prior to 2 h. By 2.5–3 h, triforine inhibited dry weight increase by 85%. The effects of triforine on protein, DNA, and RNA syntheses corresponded to the effect on dry weight increase both in time of onset and magnitude. Neither glucose nor acetate oxidation were inhibited by triforine.Ergosterol synthesis was almost completely inhibited by triforine even in the first hour after treatment. Inhibition of ergosterol synthesis was accompanied by an accumulation of the ergosterol precursors 24-methylenedihydrolanosterol, obtusifoliol, and 14α-methyl-Δ^{8, 24 (28)}-ergostadienol. Mycelia treated with 5 μg/ml of triarimol (α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol) also accumulated the same sterols as well as a fourth sterol believed to be Δ^{5, 7}-ergostadienol.Identification of 4,4-dimethyl-Δ^{8, 24 (28)}-ergostadienol in untreated mycelia indicates that the C-14 methyl group is the first methyl group removed in the biosynthesis of ergosterol by A. fumigatus. The lack of detectable quantities of 4,4-dimethyl-Δ^{8, 24 (28)}-ergostadienol in triforine or triarimol-treated mycelia and the accumulation of C-14 methylated sterols in treated mycelia suggests that both fungicides inhibit sterol C-14 demethylation. The accumulation of Δ^{5, 7}-ergostadienol in triarimol-treated mycelia further implies that triarimol also inhibits the introduction of the sterol C-22(23) double bond.Two strains of Cladosporium cucumerinum tolerant to triforine and triarimol were also tolerant to the fungicide S-1358 (N-3-pyridyl-S-n-butyl-S′-p-t-butylbenzyl imidodithiocarbonate).     

Toxicity of novel aromatic and aliphatic organic acid and ester analogs of trypsin modulating oostatic factor to larvae of the northern house mosquito, Culex pipiens complex, and the tobacco hornworm, Manduca sexta

Eight non-peptidic chemical analogs of trypsin modulating oostatic factor (TMOF, NH₂-YDPAP₆), an insect hormone inhibiting trypsin biosynthesis in mosquitoes, were synthesized based on the structure of the native peptide. The median lethal concentration (LC₅₀) for the chemical analogs, TMOF and FDPAP (a peptidic analog of TMOF) was estimated for larvae of the northern house mosquito, the Culex pipiens complex, using a static 5-day bioassay. Four of these compounds demonstrated the same larvicidal activity as TMOF, while three of these compounds were 1.2-2.5-fold more active than TMOF. The compounds introduced by injection were toxic to fourth instars of the tobacco hornworm, Manduca sexta, except for TMOF, FDPAP, and PPHEN. Injection of TMOF and FDPAP into fourth stadium and TMOF into second stadium M. sexta had no effect on trypsin activity, growth, or mortality. Apparently the mosquito hormone is inactive in the tobacco hornworm at the developmental stages examined. Three TMOF analogs (CHEA, PHEA, and PHA) demonstrating the highest activity by injection in M. sexta were also found to be toxic by injection in fourth instars of the tobacco budworm, Heliothis virescens, and the cotton bollworm, Helicoverpa zea, as well as adult male German cockroaches, Blattela germanica. A two-choice feeding bioassay with H. virescens indicated that at least one of the TMOF analogs, PHEA, has anti-feeding properties.     

Isolation of a novel Carica papaya α-amylase inhibitor with deleterious activity toward Callosobruchus maculatus

Cowpea (Vigna unguiculata) is a subsistence crop for small and poor farmers from Latin America and Africa. This culture is commonly damaged by cowpea weevil (Callosobruchus maculatus), which burrow into stored seeds to fed on. Due to impact of larval predation, several plant defense studies have been developed, indicating that α-amylase inhibitors are able to impede and/or reduce bruchids digestive process. In this report, a novel α-amylase inhibitor from papaya seeds (Carica papaya) with activity against cowpea weevil enzymes was purified and biochemical characterized. Peeled seeds were macerated and extracted with a 0.6 M NaCl and 0.1% HCl solution. Crude extract was precipitated with ammonium sulphate (100%). After dialyses, this rich fraction was applied onto a CM-Cellulose column and retained peak was submitted to an analytic reversed-phase column HPLC (Vydac C-18TP) yielding several peaks. Only one fraction, with molecular mass of 4562 Da, showed significant inhibitory activity against C. maculatus α-amylases. Otherwise, no inhibitory activities against mammalian α-amylases were observed. Bioassays using artificial seeds containing C. papaya α-amylase inhibitor rich fraction (0.5% and 1.0%) were also conduced showing that α-amylase inhibitors were able to increase larval mortality (50%) and also decrease insect fecundity and adult longevity. These results showed the presence of an α-amylase inhibitor from C. papaya seeds with high specificity to insect enzymes, indicating that this inhibitor probably could be used, through genetic engineering, in the construction of transgenic plants with enhanced resistance toward cowpea weevil.     

2-苄硫基烟酰胺类衍生物的合成及生物活性

以2-苄硫基烟酸为原料,设计并合成了26个2-苄硫基烟酰胺类化合物,其化学结构经核磁共振氢谱和元素分析确证。初步的生物活性测定结果表明,该类化合物具有一定的杀虫及除草活性。其中 C-9、C-10、C-11 在50 mg/L时对淡色库蚊Culex pipiens pallens的致死率达到100％; C-3、C-6、C-15 在100 mg/L对稗草Echinochloa crusgalli Link、马唐Digitaria sanguinalis、苋菜Ambrosia tricolor Linn的白化度大于80％。     

The breakdown of the triazine herbicide cyanazine in soils and maize

Radioisotope techniques have been used to study the breakdown products that are formed from the herbicide cyanazine ( BLADEX )^a, 2-chloro-4-(1-cyano-1-methylethyl-amino)-6-ethylamino-1,3,5-triazine, in soils and in maize grown in the soils under indoor conditions. In soils of different types cyanazine broke down mainly by conversion of the nitrile group to amide ( II ) and then to an acid ( III ) followed by hydrolysis of the ring chlorine to hydroxyl ( IV ). Dealkylation reactions occurred to only a limited extent in soils. In maize plants grown in treated soils the hydrolysis products, the amide ( II ) and the hydroxy acid ( IV ) were detected as well as appreciable quantities of products ( VI ) and ( VIII ) formed from these by loss of the N-ethyl group. In plants the hydroxy acids ( IV ) and ( VIII ) were present in the free form and there was also evidence for conjugates which were not identified but could be converted to these hydroxy acids, ( IV ) and ( VIII ), on treatment with acids. In these indoor studies the major residues appear to be the hydroxy acid ( IV ) in soils and ( IV ) and its dealkylated analogue ( VIII ) in plants grown in treated soils. These compounds are not herbicides and are of a low order of toxicity to mammals.     

Non-steroidal inhibitors of Drosophila melanogaster steroidogenic glutathione S-transferase Noppera-bo

Insect growth regulators (IGRs) can be developed by elucidating the molecular mechanisms of insect-specific biological events. Because insect molting, and metamorphosis are controlled by ecdysteroids, their biosynthetic pathways can serve as targets for IGR development. The glutathione S-transferase Noppera-bo (Nobo), which is conserved in dipteran and lepidopteran species, plays an essential role in ecdysteroid biosynthesis. Our previous study using 17β-estradiol as a molecular probe revealed that Asp113 of Drosophila melanogaster Nobo (DmNobo) is essential for its biological function. However, to develop IGRs with a greater Nobo inhibitory activity than 17β-estradiol, further structural information is warranted. Here, we report five novel non-steroidal DmNobo inhibitors. Analysis of crystal structures of complexes revealed that DmNobo binds these inhibitors in an Asp113-independent manner. Among amino acid residues at the substrate-recognition site, conformation of conserved Phe39 was dynamically altered upon inhibitor binding. Therefore, these inhibitors can serve as seed compounds for IGR development.     

Isoxaben analogs inhibit chitin synthesis in the cultured integument of the rice stem borer Chilo suppressalis

Benzoylphenylureas (BPUs) were discovered as novel type insecticides about a half century ago; many analogs have been launched as insecticides and acaricides. BPUs are known to inhibit chitin synthesis in insects and other arthropods, but they have no effect against microorganisms such as fungi. We designed new chitin synthesis inhibitors based on the hypothesis that biomolecules that play important roles in cellulose and chitin biosynthesis are similar. In the full automatic modeling system (FAMS), the cellulose synthase was selected as a template three-dimensional structure. Thus, we focused on the structure of cellulose synthase inhibitor, isoxaben, to develop new chemistry. The 1,1-diethylethyl [-C(CH₃)(CH₂CH₃)₂] group of isoxaben was changed to a 4-substituted phenyl group bearing Cl, Et, or Ph. These compounds significantly inhibited chitin synthesis in the cultured integument of the rice stem borer Chilo suppressalis. The activity of the 4-ethylphenyl analog was enhanced 30-fold by adding piperonyl butoxide to the culture medium.     

In vitro activity of sorghum-selective fluorophenyl urea herbicides

The use of N-cyclopropyl-N′-(2-fluorophenyl) urea as a selective herbicide in grain sorghum has recently been disclosed (U.S.P. 4,344,916). Evaluation of analogs of this compound has included two assays on isolated pea chloroplasts—photosynthetic electron transport and competition for atrazine binding sites. Of all the analogs studied in at least one of these assays, the most active in vitro were the N-cyclopropyl-, N-n-butyl-, and N-n-pentyl-derivatives of 2,5-difluorophenyl urea. The two in vitro assays correlated well with each other, and binding activity demonstrated a strong correlation with whole-plant phytotoxicity following postemergence application. Several postulated sorghum metabolites of N-cyclopropyl-N′-(2-fluorophenyl) urea showed weak or no activity in vitro, as would be expected from the compoud's selectivity properties.     

Fenvalerate induced stress mitigation by dietary supplementation of multispecies probiotic mixture in a tropical freshwater fish, Labeo rohita (Hamilton)

Five experimental diets with various combinations of probiotics, namely T1 & T6 (basal feed (BF) without probiotics), T2 & T7 (BF + Bacillus subtilis + Lactococcus lactis), T3 & T8 (BF + L. lactis + Saccharomyces cerevisiae), T4 & T9 (BF + B. subtilis + S. cerevisiae) and T5 & T10 (BF + B. subtilis + L. lactis + S. cerevisiae) were fed to Labeo rohita fingerlings for 30 days. Treatment groups T1, T2, T3, T4 and T5 were exposed to Fenvalerate, at a concentration of 1.79 μg L⁻¹. The SOD and CAT activity was significantly affected (P < 0.01) in fenvalerate treated groups. However, the supplementation of the three-probiotic mixture at equal concentration showed markedly reduced activity. Similarly, RBC, Hb, NBT, total protein and albumin values were reduced significantly (P < 0.01) in the fenvalerate exposed fish as compared to the probiotic supplemented fish. Fenvalerate exposure also showed increased serum ALP, ACP and Bilirubin values (P < 0.01) in comparison to the non-exposed fish. Histological observations of the gills, kidney and liver showed tissue degeneration after fenvalerate exposure, which however showed marked recovery on the three-probiotic mixture supplementation. Therefore, these results indicate that a mixture of multi-species probiotic supplementation in equal concentration acts beneficially in mitigating the stressful effects of fenvalerate.     

杨梅叶抑菌活性成分初步分离与鉴定

用石油醚、氯仿、乙酸乙酯和正丁醇分别对杨梅叶甲醇提取物进行了萃取,得不同萃取相。测定了其对番茄灰霉病菌Botrytis cinerea、番茄早疫病菌Alternaria solani、水稻立枯丝核Rhizoctonia solani、小麦禾谷镰刀菌Fusarium graminearum、 黄瓜炭疽病菌Colletotrichum lagenarium、玉米大斑病菌Setosphaeria turcica等植物病原菌的抑菌活性。结果表明,乙酸乙酯相和正丁醇相的抑菌活性较好。对乙酸乙酯相进一步分离得到7个化合物,经电喷雾质谱(ESI-MS)、核磁共振氢谱(1H NMR)和碳谱(13C NMR)鉴定其分别为已知化合物山楂酸( 1 )、3-O-反-对-香豆酰基马斯里酸( 2 )、3-O-没食子酰二氢杨梅素( 3 )、斛皮素-7-O-鼠李糖甙( 4 )、杨梅素3-O-鼠李糖甙( 5 )、杨梅素-3-O-鼠李糖(3-O-没食子酰)甙( 6 )和杨梅素-3-O-鼠李糖(2-O-没食子酰)甙( 7 )。孢子萌发法测定结果表明,化合物 3~6 对番茄灰霉病菌和玉米大斑病菌的孢子萌发具有较好的抑制作用,EC50值分别在3.44~4.59 mg/L和8.85~11.6 mg/L之间。