Evaluation of substituted oxime ethers for growth regulatory activity against Spodoptera litura (F.)

Insect growth regulatory activity (IGR) of fifty-two substituted oxime ethers were evaluated against an important polyphagous lepidopteran crop pest, Spodoptera litura (F.). A number of compounds produced symptoms comparable to exogenously applied juvenile hormone. Maximum IGR activity was exhibited by 4'-(2,6,6-trimethyl-2-cyclohexen- -yl)-3'-buten-2'(E)-ketoxime-N-O-alkyl ether with an ED50 (morphological) of 40 microg g(-1) body weight, compared to 20 microg g(-1) of JH III. Two more compounds namely 4'-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3'-buten-2'(Z)-ketoxime-N-O-methyl propyl ether (ED50 192 microg g(-1)) and 4'-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3'-buten-2'(E)-ketoxime-N-O-pentyl ether (ED50 380 microg g(-1)) showed considerable IGR activity, whereas 4'-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3'-buten-2'(E)-ketoxime-N-O-pentyl ether was found to be toxic to the larvae (ED50 268 microg g(-1)). Three compounds used in this study were also synergised by piperonyl butoxide (PBO). The synergistic ratios were found in the range of 1.33 to 4.605. The ovicidal activity of the oxime ethers is not significant.     

Evaluation of substituted oxime ethers for growth regulatory activity against Spodoptera litura (Lepidoptera: Noctuidae)

Insect growth regulator (IGR) activity of 52 substituted oxime ethers was evaluated against an important polyphagous lepidopteran pest, Spodoptera litura (F.) (Lepidoptera: Noctuidae). Several compounds produced symptoms comparable to exogenously applied juvenile hormone. Maximum ICR activity was exhibited by 4'-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3'-buten-2'(E)-ketoxime-N-O-alkyl ether with an ED50 (morphological) of 40 microg g(-1) body weight, compared with 20 microg g(-1) of juvenile hormone (JH) III. Two more compounds, namely, 4'-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3'-buten-2'(Z)-ketoxime-N-O-methyl propyl ether (ED50 of 192 microg g(-1)) and 4'-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3'-buten-2'(E)-ketoxime-N-O-pentyl ether (ED50 of 380 microg g(-1)) showed considerable IGR activity, whereas 4'-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3'-buten-2'(E)-ketoxime-N-O-pentyl ether was found to be acutely toxic to larvae (ED50 of 268 microg g(-1)). Three compounds used in this study also were synergized by piperonyl butoxide. Synergistic ratios ranged from 1.330 to 4.605. No significant ovicidal activity was obtained.     

Determination of the lipid peroxidation product (E)-4-hydroxy-2-nonenal in clinical samples by gas chromatography-negative-ion chemical ionisation mass spectrometry of the O-pnetafluorobenzyl oxime

(E)-4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the free radical-stimulated lipid peroxidation of phospholipid-bound arachidonic acid in cellular membranes. We describe a sensitive and specific method for the determination of HNE in clinical samples. The method is based on the formation of the O-pentafluorobenzyl (O-PFB) oxime derivative of HNE, which is then extracted and cleaned up by solid-phase extraction. The HNE O-PFB oxime is then analysed without further derivatisation by capillary column gas chromatography-negative ion chemical ionisation mass spectrometry (GC-NICI-MS) using selected-monitoring. Concentrations down to the pmol range were achieved using deuterated HNE as an internal standard. The method was used to determine HNE in the cerebrospinal fluid and plasma of patients with Parkinson's disease, the plasma of patients with HIV-1 infection and AIDS and in inflamed mucosal biopsy specimens from patients with inflammatory bowel disease.     

Ether lipids

The naturally occurring 1-O-alkyl-sn-glycerols and their methoxylated congeners, 1-O-(2′-methoxyalkyl)-sn-glycerols, are biologically active compounds, ubiquitously found in nature as diacyl glyceryl ether lipids and phosphoether lipids. The chief objective of this article is to provide a comprehensive and up to date review on such ether lipids. The occurrence and distribution of these compounds in nature are extensively reviewed, their chemical structure and molecular variety, their biosynthesis and chemical synthesis and, finally, their various biological effects are described and discussed. An unprecedented biosynthesis of the 2′-methoxylated alkylglycerols is proposed. The first synthesis of enantiopure (Z)-(2′R)-1-O-(2′-methoxyhexadec-4′-enyl)-sn-glycerol, the most prevalent 2′-methoxylated type alkylglycerol present in cartilaginous fish, is described. It was accomplished by a highly convergent five step process.     

Semisynthesis and Antifungal Activity of Novel Oxime Ester Derivatives of Carabrone Modified at C(4) against Botrytis cinerea

To continuously improve the potential utility of the natural lead compound of carabrone in agrochemistry, carabrone oxime and 36 novel oxime ester derivatives of carabrone modified at C(4) were synthesized, and evaluated for their antifungal activities against Botrytis cinerea in vitro and in vivo. Of these 36 oxime ester derivatives, some compounds exhibited antifungal activities in vitro or in vivo. It was found that compounds with a pyridinyl residue can either efficiently inhibit spore germination or efficiently inhibit hyphal growth of B. cinerea, and compound 9 exhibited the highest activity in vitro and in vivo with IC₅₀ and EC₅₀ values of 1.17 and 12.9 μg/ml, respectively. Further, the structure? activity relationships are also discussed.     

Imidazolylchromanone oxime ethers as potential anticonvulsant agents: Anticonvulsive evaluation in PTZ-kindling model of epilepsy and SAR study

As a continuation of our efforts to develop the azolylchromanone derivatives as potential anticonvulsant agents, we explored (Z)- and (E)-oxime ether derivatives of imidazolylchromanones bearing different lipophilic O-benzyl groups and tested their anticonvulsant activities in PTZ-kindling model of epilepsy. O-(2,4-Dichlorobenzyl) oximes 8a, 16a and 20a were significantly effective in delaying the onset of the PTZ-evoked seizures at the dose of 30 mg/kg in kindled animals. The most effective compounds in delaying seizures were 7-chlorochromanone-O-(2,4-dichlorobenzyl) oximes 8a and 20a. SAR studies showed that introduction of a chlorine atom to the 7-position and/or a methyl group to the 2-position of the chroman ring resulted in an improvement of anti-seizure efficacy in O-(2,4-dichlorobenzyl) oxime series.     

Stereoselective synthesis of (1-alkoxyalkyl) α- and β-d-glucopyranosiduronates (acetal-glucopyranosiduronates): A new approach to specific cytostatics for the treatment of cancer

The reaction of methyl 2,3,4,6-tetra-O-acetyl-1-O-trimethylsilyl-β- (5) and -α-d-glucopyranuronate (6) severally with the dimethyl or diethyl acetals of formaldehyde, bromoacetaldehyde, propionaldehyde, 3-benzyloxypropionaldehyde, 5-carboxypentanal, and 2-bromohexanal in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate at −78° gave the corresponding (1-alkoxyalkyl) α- and β-glycosides (acetal-glucopyranosiduronates) with retention of configuration at C-1 in yields of 41–91%. Instead of the dialkyl acetals, the corresponding aldehydes and alkyl trimethylsilyl ether can be used. Deacetylation gave the corresponding methyl (acetal-β- and -α-d-glucopyranosid)uronates in good yield. De-esterification of methyl [(1R)-1-methoxybutyl β-d-glucopyranosid]uronate with esterase gave the acetal-β-d-glucopyranosiduronic acid which was an excellent substrate for β-d-glucuronidase.     

New Phenylpropanoid Glycosides from Illicium majus and Their Radical Scavenging Activities

Chemical investigation of the ethanol extract of the branch and leaves of Illicium majus resulted in the isolation of four new phenylpropanoid glycosides ( 1 – 4 ) and one new phenolic glycoside ( 9 ), along with 13 known ones. Spectroscopic techniques were used to elucidate the structures of the new isolates such as 3-[(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-yl]propyl β-D-glucopyranoside ( 1 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-glucopyranoside ( 2 ), [(2R,3S)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-5-(3-hydroxypropyl)-2,3-dihydro-1-benzofuran-3-yl]methyl 2-O-α-L-rhamnopyranosyl-β-D-xylopyranoside ( 3 ), 3-[(2R,3S)-3-({[2-O-(4-O-acetyl-α-L-rhamnopyranosyl)-β-D-xylopyranosyl]oxy}methyl)-7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-2,3-dihydro-1-benzofuran-5-yl]propyl acetate ( 4 ), and 4-(2-hydroxyethyl)phenyl 3-O-β-D-glucopyranosyl-β-D-glucopyranoside ( 9 ). Free radical scavenging activities of the isolates were elucidated through the DPPH assay method. The most active compounds, 1-O-caffeoyl-β-D-glucopyranose ( 17 ) and soulieana acid 1 ( 18 ), exhibited moderate radical scavenging activities (IC₅₀=37.7±4.4 μM and IC₅₀=97.2±3.4 μM, respectively). The antibacterial activities of the isolates against Staphylococcus aureus and Escherichia coli were also assessed, and no activity was shown at the measured concentration (<32 μg/mL).     

Oxidative and hydrolytic transformations of hydroxylamine compounds in cyanobacteria

Ammonia-incubated cyanobacteria liberated H₂O₂, accumulated hydroxylamine compounds and nitrite and catalyzed dismutation of hydroxylamine as well as oxidations of ammonia, glutamine, and oximes. Ethyl acetohydroximate-adapted Phormidium released excess H₂O₂ and phototrophically metabolized the oxime via hydrolysis and dismutation to nitrite and ammonia, which were consumed by nitrite reductase and glutamine synthetase. Added ammonia stimulated H₂O₂ production and oxime metabolism via glutamate dehydrogenase pathway.Abbreviations EAH Ethyl acetohydroximate - GDH glutamate dehydrogenase - GS glutamine synthetase - NiR nitrite reductase     

Facile synthesis and stereochemical investigation of Mannich base derivatives: evaluation of antioxidant property and antituberculostic potency

A mini-library of diversely substituted 2,4-diaryl-3-azabicyco[3.3.1]nonan-9-one O-methyloximes and their N-methyl analogs were synthesized by a non-laborious, modified and an optimized Mannich condensation in good yields. Both the ring N-methylation and oxime O-methylation were employed by various methods; of them, the usage of ^tBuOK was found to be the superior in terms of good yield in short time. Stereochemistry of all the synthesized compounds was unambiguously established by their NMR spectral (¹H, ¹³C, ¹H-¹H COSY, ¹H-¹³C one and multiple bond COSY and NOESY) as well as single-crystal XRD studies. Irrespective of the nature and position of the substituents, all the synthesized oxime ethers of the bicyclic Mannich bases as well as their N-methyl analogs adopted the twin-chair conformation with equatorial orientations of all the substituents. All the synthesized oxime ethers were evaluated for their antioxidant property by DPPH radical scavenging method. According to the structure-activity correlations, compound 4y was found to be a lead molecule with the IC₅₀ of 0.187 mg/mL. Thus, the present study exploits the scope of finding more active analogs by further optimization with the incorporation of more electron enriched alkoxy/amino and/or phenolic groups on the heterocycle as well as oxime ether pharmacophore. Most of the synthesized molecules were screened for their antituberculostic potency against Mycobacterium tuberculosis H₃₇Rv by zone of inhibition method. Of them, 4w/5d and 4x showed very promising inhibition zones of 21 and 23 mm, respectively, which leads to the optimization of 4x by introducing various substituents on the O-benzyl moiety to enhance the antituberculostic potency.     

Synthesis and antiproliferative evaluation of 6-aryl-11-iminoindeno[1,2-c]quinoline derivatives

A number of 6-aryl-11-iminoindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities. Among them, (E)-6-{4-[3-(dimethylamino)propoxy]phenyl}-2-fluoro-9-hydroxy-11H-indeno[1,2-c]quinolin-11-one O-3-(dimethylamino)propyl oxime (23a) was the most active, exhibited GI₅₀ values of 0.64, 0.39, 0.55, 0.67, and 0.65 μM against the growth of Hep G2, Hep 3B, A549, H1299, and MDA-MB-231, respectively. Compound 23a inhibited the growth of hepatoma cell lines in a dose- and time-dependent manner. The proportion of cells was decreased in the G1 and accumulated in G2/M phase after 12 h treatment of 23a, while the hypodiploid (sub-G0/G1 phase) cells increased. Further investigations have shown that 23a induced cell cycle arrest at G2/M phase and induce apoptosis via activation of p53, Bax, and caspase-8 which consequently cause cell death.     

Synthesis and in vitro antiproliferative evaluation of d-secooxime derivatives of 13β- and 13α-estrone

d-Secooximes were synthesized from the d-secoaldehydes in the 13β- and 13α-estrone series. The oximes were modified at three sites in the molecule: the oxime function was transformed into an oxime ether, oxime ester or nitrile group, the propenyl side-chain was saturated and the 3-benzyl ether was removed in order to obtain a phenolic hydroxy function. Triazoles were formed via Cu(I)-catalysed azide–alkyne cycloaddition (CuAAC) from 3-(prop-2-yniloxy)-d-secooximes and benzyl azides. All the products were evaluated in vitro by means of MTT assays for antiproliferative activity against a panel of human adherent cell lines (HeLa, MCF-7, A2780 and A431). Some of them exhibited activities with submicromolar IC₅₀ values, better than that of the reference agent cisplatin. The structural modifications led to significant differences in the cytostatic properties. Flow cytometry indicated that one of the most potent agents resulted in a cell cycle blockade.     

Synthesis and antimicrobial activity of novel fluorine containing 4-(substituted-2-hydroxybenzoyl)-1H-pyrazoles and pyrazolyl benzo[d]oxazoles

A series of fluorine containing 4-(substituted-2-hydroxybenzoyl) pyrazoles and pyrazolyl benzo[d]oxazoles were synthesized and evaluated for their antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis and antifungal activity against Candida albicans. The antibacterial activities were expressed as the minimum inhibitory concentration (MIC₅₀) in μg/ml. The compounds 1-(3,4-difluorophenyl)-4-(5-fluoro-2-hydroxybenzoyl)-1H-pyrazole (4b), oxime derivatives such as 1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)(2-hydroxy-4-methylphenyl)methanone oxime (5b) and (5-chloro-2-hydroxyphenyl)(1-(3,4-difluorophenyl)-1H-pyrazol-4-yl)methanone oxime (5e) exhibited promising activities against tested bacterial strains. Except compound 1-(3,4-difluorophenyl)-4-(2-hydroxybenzoyl)-1H-pyrazole (4d), none of the other compounds showed promising antifungal activity.     

Identification of Ether à Go-Go and Calcium-Activated Potassium Channels in Human Melanoma Cells

Ion channels and intracellular Ca²⁺ are thought to be involved in cell proliferation and may play a role in tumor development. We therefore characterized Ca²⁺-regulated potassium channels in the human melanoma cell lines IGR1, IPC298, and IGR39 using electrophysiological and molecular biological methods. All cell lines expressed outwardly rectifying K⁺ channels. Rapidly activating delayed rectifier channels were detected in IGR39 cells. The activation kinetics of voltage-gated K⁺ channels in IRG1 and IPC298 cells displayed characteristics of ether à go-go (eag) channels as they were much slower and depended both on the holding potential and on extracellular Mg²⁺. In addition, they could be blocked by physiological concentrations of intracellular Ca²⁺. In accordance with these electrophysiological results, analysis of mRNA revealed the expression of a gene coding for h-eag1 channels in IGR1 and IPC298 cells, but not in IGR39 cells. At elevated Ca²⁺ concentrations various types of Ca²⁺-activated K⁺ channels with single-channel characteristics similar to IK and SK channels were detected in IGR1 cells. The whole-cell Ca²⁺-activated K⁺ currents were not voltage dependent, insensitive for 100 nm apamin and 200 μm d-tubocurarine, but were blocked by charybdotoxin (100 nm) and clotrimazole (50 nm). Analysis of mRNA revealed the expression of hSK1, hSK2, and hIK channels in IGR1 cells. Received: 5 February 1999/Revised: 28 May 1999     

Control of potato cyst-nematode, Heterodera rostochiensis, in silt and peat loams by ten pesticides applied to the soil at planting time

Incorporated in silt or peat loam top-soil in spring before susceptible potatoes were planted, three carbamoyl oximes, aldicarb, Tirpate (2,4-dimethyl-2-formyl 1-1,3-dithiolane oxime iV-methylcarbamate) and Du Pont 1410 (S-methyl i-(dimethylcarbamoyl)-N-((methylcarbamoyl) oxy) thioformimidate) and one organophosphate, Nemacur (O-ethyl-O-(3-methyl-4-methylthiophenyl)-isopropylamidophosphate) all at n-2 kg a.i./ha greatly increased the yield of tubers and effectively controlled potato cyst-nematode (Heterodera rostochiensis Woll.). At the same dosage thionazin was as effective in the peat loam but was ineffective in the silt loam; phorate and Mocap (O-ethyl S,S-dipropyl phosphorodithioate) were less effective and chlorfenvinphos, diazinon and a coarse granule formulation of fensulphothion were ineffective in controlling potato cyst-nematode.     

Synthesis and fungicidal activities of novel benzothiophene-substituted oxime ether strobilurins

Twenty-one novel benzothiophene-substituted oxime ether strobilurins, which employed a benzothiophene group to stabilise the E-styryl group in Enoxastrobin (an unsaturated oxime strobilurin fungicide developed by Shenyang Research Institute of Chemical Industry, China) were designed and synthesised. The biological assay indicated that most compounds exhibited good or excellent fungicidal activities, especially against Colletotrichum lagenarium and Puccinia sorghi Schw. In addition, methyl 3-methoxypropenoate oxime ethers and N-methoxy-carbamic acid methyl esters exhibited good in vivo fungicidal activities against Erysiphe graminis, Colletotrichum lagenarium and Puccinia sorghi Schw. under the tested concentrations. Notably, (E,E)-methyl 3-methoxy-2-(2-((((6-chloro-1-(1H-benzo[b]thien-2-yl)ethylidene)amino)oxy)methyl)phenyl)propenoate (5E) exhibited more potent in vivo fungicidal activities against nearly all of the tested fungi at a concentration of 0.39 mg/L compared to Enoxastrobin.     

Synthesis of C-(d-glycopyranosyl)ethylamines and C-(d-glycofuranosyl)methylamines as potential glycosidase inhibitors

The C-glucosyl aldehyde, 2-C-(2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl)ethanal was prepared from the C-glucopyranosyl propene precursor by ozonolysis. Reductive amination of the C-glucosyl aldehyde and subsequent deprotection gave 1-anilino-2-C-(α-d-glucopyranosyl)ethane. The E and Z isomers of the oxime derivative, 1-C-(α-d-arabinofuranosyl)methanal oxime were prepared by treating their aldehyde precursor with hydroxylamine. Acetylation of the oxime, followed by catalytic hydrogenation and deprotection, gave the corresponding 1-C-(α-d-arabinofuranosyl)methylamine. Reductive amination of ethyl 2,3-O-isopropylidene-α-d-lyxo-pentodialdo-1,4-furanoside using aniline gave ethyl 5-anilino-5-deoxy-d-lyxo-furanoside. Inhibition studies with these compounds on β-d-glucosidase from sweet almond, using o-nitrophenyl d-glucopyranoside as substrate, were carried out.     

Synthesis of thiazole-based substituted piperidinone oximes: Profiling of antioxidant and antimicrobial activity

The synthesis of novel thiazole-based piperidinone oximes and screening of their antioxidant and antimicrobial activity are described. The obtained results revealed that the electronic effects of active substituents at C-4 terminals of phenyl rings on either side of piperidinone skeleton, as well as at 2-hydrazinyl thiazole, played a major role in development of antioxidant and antimicrobial activity. Antioxidant activity seems to be based also on radical dissipating ability of the thiazole ring. The nucleophilic character of sulfur in thiazole and lipophilic nature of piperidinone skeleton substantially influenced the observed antimicrobial activity of thiazole-based piperidinone oximes. Among the synthesized compounds, 2,6-bis(4-hydroxy-3-methoxyphenyl)-1-methylpiperidin-4-one O-(2-(2-(4-hydroxy-3-methoxybenzylidene)hydrazinyl)thiazol-4-yl) oxime exhibited excellent antioxidant activity whereas compound 2,6-bis(4-chloro phenyl)-1-methylpiperidin-4-one O-(2-(2-(4-nitrobenzylidene)hydrazinyl)thiazol-4-yl)oxime emerged as an outstanding antimicrobial agent.     

Facile Synthesis of 4-O-β-N-Acetylchitooligosyl 2-acetamido-2,3-dideoxydidehydro-gluconolactone Based on the Transformation of Chitooligosaccharide and Its Suppressive Effects against the Furylfuramide-Induced SOS Response

A facile synthesis method is described for transforming the reducing-end residue of chitooligosaccharides (DP 2–4) into lactone. The desired 4-O-β-N-acetylchitooligosyl lactones (GN_nL) were conveniently prepared from chitooligosaccharides by consecutive dehydration and oxidation reactions to afford 4-O-β-tri-N-acetylchitotriosyl 2-acetamido-2,3-dideoxydidehydro-gluconolactone (GN₃L), 4-O-β-di-N-acetylchitobiosyl 2-acetamido-2,3-dideoxydidehydro-gluconolactone (GN₂L), and 4-O-β-2-acetamido-2-deoxy-D-glucopyranosyl 2-acetamido-2,3-dideoxydidehydro-gluconolactone (GNL). The resulting lactone derivatives exhibited considerable suppression (42.6–54.3% at a concentration of 400 µM) in umu gene expression of the SOS response in Salmonella typhimurium TA1535/pSK1002 against the mutagen, 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamido (AF-2). Lactonization of the chitooligosaccharides was found to be essential for their suppression of the SOS-inducing activity.     

Investigations on the metabolic stability of cytosolic phospholipase A2α inhibitors with 1-indolylpropan-2-one structure

Cytosolic phospholipase A₂α (cPLA₂α) plays a key role in the pathogenesis of many inflammatory diseases, such as rheumatoid arthritis, atopic dermatitis and Alzheimer’s disease. Therefore, inhibition of this enzyme is assumed to provide a novel therapeutic option for the treatment of these maladies. In this study we investigated the metabolism of the potent cPLA₂α inhibitors 1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (1) and 3-isobutanoyl-1-[3-(4-phenoxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2). Incubation of 1 with a mixture of human recombinant CYP1A2, 2C8, 2C9, 2C19, 2D6, 3A4 and NADPH-cytochrome P450 reductase enzymes led to reduction of its keto group and to hydroxylation at the terminal phenoxy residue. To identify the enzymes responsible for the observed reactions, experiments with isoform inhibitors were performed. In rat liver S9 fractions the only metabolite found was the alcohol 3 formed by the reduction of the keto group of 1. This reaction here was mainly catalyzed by cytosolic short-chain dehydrogenases/reductases (cSDR) as shown by inhibition experiments with different carbonyl reductase inhibitors. Furthermore, the metabolic stability of 2 in mouse brains was studied after intracerebroventricular application of this compound into the right brain hemispheres of mice. HPLC/MS analyses revealed that 2 is also readily reduced in the brain to an inactive alcohol metabolite most likely by carbonyl reductases.