Search Results (60)

The ionotropic γ-aminobutyric acid (GABA) receptor (GABAR) is a key target for the development of antiparasitic agents, particularly against ectoparasites, such as fleas and ticks. Binding stability and selectivity of sarolaner enantiomers for Ctenocephalides felis RDL receptors (RDLR) were investigated in the current study. Wild-type (WT) C. felis RDLR and its A285S mutant were constructed using homology-based, fragment-based threading and AI-driven approaches, of which, SWISS-MODEL generated the most reliable structures. Molecular docking showed that the sarolaner S-enantiomer had higher binding affinity for both receptors than the R-enantiomer, primarily due to hydrogen bonding with Ile256, π–π stacking with Phe326, and hydrophobic interactions with Ile267 and Ile268. Molecular dynamics simulations confirmed the binding stability of the S-enantiomer-receptor complex in which key residues maintained interactions throughout the trajectories. Binding free energy analysis supported these results and highlighted the role of nonpolar interactions in binding stability. The A285S mutation had minimal impact on the binding pocket, and the S-enantiomer remained selective for and bound to the mutant receptor. Insights into the insecticidal mechanism of sarolaner enantiomers are given, and the current findings may inform the development of veterinary drugs from novel isoxazoline-based NAMs targeting insect GABARs. Full article

The search for new heterocyclic compounds with biological potential is one of the current challenges in modern chemistry. Therefore, the comprehensive study of (3 + 2) cycloaddition (32CA) reactions between a series of aryl-substituted nitrile N-oxides (NOs) and (E)-3,3,3-tribromo-1-nitroprop-1-ene (TBNP) is carried out. According to the experimental research, in all tested 32CAs, the proper (4RS,5RS)-3-aryl-4-nitro-5-tribromomethyl-2-isoxazolines are obtained as only one reaction product. In turn, the quantum–chemical MEDT study shows that the creation of heterocycles occur via the polar attack of zwitterionic moderate-nucleophilic NOs to strong electrophilic TBNP. The reactions are realized according to a two-stage, one-step asynchronous mechanism, in which the formation of the O-C(CBr₃) bond takes place once the C-C(NO₂) bond is already formed. What is more, the computational analysis confirmed the experimental results. At the end, the obtained 2-isoxazolines were docked to three proteins: gelatinase B, cyclooxygenase COX-1, and Caspase-7. We hope that the presented study will be helpful for searching for the future direction of application for this class of organic compounds. Full article

Fluxametamide, an innovative isoxazoline insecticide, acts as an antagonist of γ-aminobutyric acid-gated chloride channels. Its distinct mode of action sets it apart, lacking known cross-resistance with current insecticides. This positions fluxametamide as a promising tool for addressing insecticide resistance in Lepidoptera, thysanoptera, coleoptera, and diptera pest insects. To develop and implement successful resistance management strategies, it is crucial to establish the baseline susceptibility to this insecticide before it is registered and widely used in China. In this study, we assessed the baseline susceptibility of two widespread lepidopteran pest species, Plutella xylostella and Spodoptera exigua, to fluxametamide. The insecticide exhibited remarkably high efficacy against populations of the two lepidopteran species sampled in their primary distribution areas in China. For P. xylostella and S. exigua, the median lethal concentrations (LC₅₀) ranged between 0.040 and 0.247 mg/L, and 0.211 and 0.761 mg/L, respectively. Among populations, there was a relative low variability in susceptibility to fluxametamide, showing a 6.18-fold difference for P. xylostella and 3.61-fold for S. exigua. The suggested diagnostic concentrations for P. xylostella and S. exigua were 10 and 15 mg/L, respectively. Fluxametamide exhibited high toxicity to the selected resistant strains, which displayed strong resistance to abamectin, emamectin benzoate, and deltamethrin. No cross-resistance to fluxametamide was detected in the laboratory diamide-resistant strain. Our findings offer essential insights for crafting successful resistance management initiatives to maintain the effectiveness of fluxametamide against these significant pests. Full article

Isocycloseram is a novel insecticide belonging to the class of isoxazoline (IRAC MoA Group 30) that exhibits excellent efficacy and selectivity against invertebrate pests. We evaluated the efficacy of two 0.1% isocycloseram formulations against a laboratory and four insecticide-resistant field strains of common bed bugs (Cimex lectularius L.) (Hemiptera: Cimicidae) by direct spray and forced exposure on three surfaces (fabric, vinyl tiles, and unpainted pinewood). Their efficacy was compared with that of five commercial insecticides including Demand CS (0.03% λ-cyhalothrin), Temprid FX (0.05% imidacloprid and 0.025% β-cyfluthrin), Crossfire (0.4% clothianidin, 0.01% metofluthrin, and 1.0% piperonyl butoxide), Bedlam Plus (0.4% d-phenothrin, 1.0% MGK 264, and 0.05% imidacloprid), and PT Phantom II (0.5% chlorfenapyr). Both isocycloseram 45 SC and 400 SC formulations were the most effective among the tested insecticides. The isocycloseram 45 SC formulation caused faster mortality than the 400 SC formulation. Four hours of exposure to 0.025, 0.05, and 0.1% isocycloseram 45 SC residue on porous and non-porous surfaces caused 100% bed bug mortality after 3–4 days. Exposure to 30-day-aged 0.1% isocycloseram 45 SC residue for 4 h still caused 100% mortality, compared to 0–73% mortality by the five commercial insecticides. Isocycloseram is a highly effective compound for controlling resistant C. lectularius populations. Full article

Isoxazole derivatives (isoxazoles, isoxazolines, and isoxazolidines) are present in the structure of several natural products and/or pharmaceutically interesting compounds. In this work, a synthetic study for the preparation of fused isoxazoline/isoquinolinone hybrids is presented. The initial approach involving the sequential 1,3-dipolar cycloaddition of nitrile oxides to indenone (to obtain the isoxazoline ring) and a Beckmann rearrangement (to construct the isoquinolinone lactam system) was complicated by the formation of fragmentation products during the latter. Therefore, the desired hybrids were successfully reached by applying DDQ-mediated oxidation of the respective isoxazolidines. Based on the results, key observations were made regarding the mechanism of the Beckmann reaction. Moreover, selected isoxazole benzamides and fused isoxazoline/isoxazolidine isoquinolinones were in vitro evaluated against a series of fungi strains (including a 2D checkerboard assay with ketoconazole), revealing that some of these compounds exhibit promising antifungal activity. Full article

The microwave-assisted 1,3-dipolar cycloaddition reaction of several aldoximes and dimethyl-2-methylene glutarate in the presence of diacetoxyiodobenzene as an oxidant produced four new isoxazoline-derived dimethyl carboxylates. Saponification followed by acidification of the latter yielded novel isoxazoline dicarboxylic acids in reasonable to high yields. The structures of these novel compounds were characterized by IR, ¹H-NMR, ¹³C-NMR, and HRMS spectroscopy. Their biological activities disclosed higher inhibition of the growth of E. coli organisms by the aromatic compounds than by the aliphatic derivatives, demonstrating their potential in antibiotics research. Full article

This study examined the chemoselectivity and diastereoselectivity of silyl nitronate alkenyn-nitroethers in Intramolecular Silyl Nitronate Cycloadditions (ISNCs) to produce isoxazole derivatives with interesting medicinal properties. These reactions resulted in the formation of either dihydrofuro[3,4-c]isoxazolines/isoxazolidines and/or alkynyl moieties attached to 2,5-dihydrofuryl carbonyls. This study also discerned the diastereoselectivities of the resulting cyclic adducts and compared them to previous findings. The reactions were also investigated with Spartan molecular modeling computations to aid in the understanding of any displayed chemo- and/or stereoselectivity. These [3+2]-cycloaddition reactions demonstrated excellent to complete chemospecificity. The cycloadditions also demonstrated remarkable diastereospecificity in that each diastereomer of the nitroethers resulted in the formation of only one of four possible diastereomeric outcomes. The stereochemistry of the major diastereomers did not agree with previously published findings. Full article

Oximation of substituted ketofurfuryl alcohols in the presence of hydroxylamine hydrochloride and pyridine in ethanol as solvent led to a new class of spiro derivatives presenting a 7-methylene-1,6-dioxa-2-azaspiro [4.4] nona-2,8-diene skeleton along with, in some cases, the predictable oxime. The structures of such spiro compounds were determined by 2D NMR spectroscopy. The suggested formation of this skeleton involves an in situ oximation/dehydration/S_N’ cascade reaction. Full article

The cycloaddition of nitrile oxides and nitrilimines to one or both of the C=C double bonds of caryophyllene is described. The possibility of introducing five-membered fused and spiro-linked heterocycles into the structure of sesquiterpenes by the 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrilimines to caryophyllene was demonstrated. As a result of these reactions, pharmacophore fragments of isoxazoline and pyrazoline are introduced into the structure of caryophyllene, which leads to an increase in the conformational rigidity of the molecule. A complete stereochemical assignment of 1,3-dipolar cycloaddition adducts to caryophyllene was carried out. The study of antiviral and cytotoxic activity for some heterocyclic derivatives synthesized in this work revealed relatively high biological activity of previously little-studied cycloaddition adducts at the exocyclic C=CH₂ bond of caryophyllene. The effect of substituents in the synthesized heterocycles on biological activity was demonstrated. Compounds with a good inhibitory effect on the H1N1 influenza virus were revealed. The activity of the compound was demonstrated up to 6 h post infection, and this could be due to slight inhibiting activity against viral neuraminidase, necessary at the stage of progeny virion budding. Full article

Grass pea (Lathyrus sativus L.) is a protein-rich crop that is resilient to various abiotic stresses, including drought. However, it is not cultivated widely for human consumption due to the neurotoxin β-N-oxalyl-L-α, β-diaminopropionic acid (β-ODAP) and its association with neurolathyrism. Though some varieties with low β-ODAP have been developed through classical breeding, the β-ODAP content is increasing due to genotype x environment interactions. This review covers grass pea nutritional quality, β-ODAP biosynthesis, mechanism of paralysis, traditional ways to reduce β-ODAP, candidate genes for boosting sulfur-containing amino acids, and the potential and targets of gene editing to reduce β-ODAP content. Recently, two key enzymes (β-ODAP synthase and β-cyanoalanine synthase) have been identified in the biosynthetic pathway of β-ODAP. We proposed four strategies through which the genes encoding these enzymes can be targeted and suppressed using CRISPR/Cas9 gene editing. Compared to its homology in Medicago truncatula, the grass pea β-ODAP synthase gene sequence and β-cyanoalanine synthase showed 62.9% and 95% similarity, respectively. The β-ODAP synthase converts the final intermediate L-DAPA into toxic β-ODAP, whist β-cyanoalanine synthase converts O-Acetylserine into β-isoxazolin-5-on-2-yl-alanine. Since grass pea is low in methionine and cysteine amino acids, improvement of these amino acids is also needed to boost its protein content. This review contains useful resources for grass pea improvement while also offering potential gene editing strategies to lower β-ODAP levels. Full article

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a–5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a “click chemistry” approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including ¹H NMR, ¹³C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of −9.9 and −9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski’s criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development. Full article

Regioselectivity and the molecular mechanism of the [3+2] cycloaddition reaction between nitro-substituted formonitrile N-oxide 1 and electron-rich alkenes were explored on the basis of the wb97xd/6-311+G(d) (PCM) quantum chemical calculations. It was established that the thermodynamic factors allow for the formation of stable cycloadducts along all considered models. The analysis of the kinetic parameters of the main processes show that all [3+2] cycloadditions should be realized with full regioselectivity. In all cases, the formation of 5-substituted 3-nitro-2-isoxazolidines is clearly preferred. It is interesting that regiodirection is not determined by the local electrophile/nucleophile interactions but by steric effects. From a mechanistic point of view, all considered reactions should be treated as polar, one-step reactions. All attempts to locate the hypothetical zwitterionic intermediates along the cycloaddition paths were, however, not successful. Full article

Ionotropic γ-aminobutyric acid (GABA) receptors in insects, specifically those composed of the RDL (resistant to dieldrin) subunit, serve as important targets for commonly used synthetic insecticides. These insecticides belong to various chemical classes, such as phenylpyrazoles, cyclodienes, meta-diamides, and isoxazolines, with the latter two potentially binding to the transmembrane inter-subunit pocket. However, the specific amino acid residues that contribute to the high sensitivity of insect RDL receptors to these novel insecticides remain elusive. In this study, we investigated the susceptibility of seven distinct Drosophila melanogaster Rdl point mutants against four meta-diamide and isoxazoline insecticides: isocycloseram, fluxametamide, fluralaner, and broflanilide. Our findings indicate that, despite exhibiting increased sensitivity to fluralaner in vitro, the Rdl^I276C mutant showed resistance to isocycloseram and fluxametamide. Similarly, the double-points mutant Rdl^I276F+G279S also showed decreased sensitivity to the tested isoxazolines. On the other hand, the Rdl^G335M mutant displayed high levels of resistance to all tested insecticides. Molecular modeling and docking simulations further supported these findings, highlighting similar binding poses for these insecticides. In summary, our research provides robust in vivo evidence supporting the idea that the inter-subunit amino acids within transmembrane M1 and M3 domains form the binding site crucial for meta-diamide and isoxazoline insecticide interactions. This study highlights the complex interplay between mutations and insecticide susceptibility, paving the way for more targeted pest control strategies. Full article

A practical metal-free and additive-free approach for the synthesis of 6/7/8-membered oxacyclic ketone-fused isoxazoles/isoxazolines tetracyclic or tricyclic structures is reported through C_sp³–H bond radical nitrile oxidation and the intramolecular cycloaddition of alkenyl/alkynyl-substituted aryl methyl ketones. This convenient approach enables the simultaneous formation of isoxazole/isoxazoline and 6/7/8-membered oxacyclic ketones to form polycyclic architectures by using tert-butyl nitrite (TBN) as a non-metallic radical initiator and N–O fragment donor. Full article

Naphtho[1,8-de][1,2]oxazin-4-ol and its acyl or benzyl derivatives ring open to various 2,8-dihydroxy-1-naphthonitriles, which, through (de)protection protocols and reduction, afford the target (E)-2-hydroxy-8-methoxy-1-naphthaldehyde. This was converted to its corresponding oxime, which was oxidatively o-cyclized with phenyliodine(III) diacetate (PIDA) to 9-methoxynaphtho[1,2-d]isoxazole 2-oxide. The latter, in deuterated DMSO at room temperature, was rearranged to its isomer 2-hydroxy-8-methoxy(naphthalen-1-yl)nitrile oxide. The isomerization was detected by time-course plot ¹H NMR spectroscopy and further identified from its ¹³C NMR and HRMS spectra. The nitrile oxide was stable in (non)deuterated DMSO for at least 18 h. A 3,4-bis(2-hydroxy-8-methoxynaphthalen-1-yl)-1,2,5-oxadiazole 2-oxide, as a dimerization product or an isocyanate as a rearrangement isomer, was ruled out, the former by its HRMS spectrum and the latter by its 1,3-dipolar cycloaddition reactions to substituted isoxazoles. Full article