Ether Derivatives Research Articles

Synthesis and Insecticidal Activity Study of Azidopyridryl Containing Dichlorolpropene Ether Derivatives.

Pyridalyl, as a novel insecticide with an unknown mode of action, has shown excellent control efficacy against lepidopterous larvae and thrips. Previous modifications of this compound have mostly focused on the pyridine moiety, with limited information available about modifications to other parts of pyridalyl. In this paper, we report the synthesis and insecticidal activity of a series of azidopyridryl-containing dichlorolpropene ether derivatives, based on modifications to the middle alkyl chain of pyridalyl. Screening results for insecticidal activity indicate that our synthesized compounds show moderate to high activities at the tested concentrations against P. xylostella. Particularly, compound III-10 exhibits a LC50 value of 0.831 mg L-1, compared to the LC50 value of pyridalyl at 2.021 mg L-1. Furthermore, compound III-10 also displays a relatively broad insecticidal spectrum against Lepidoptera pests M. separata, C. suppressalis, O. nubilalis, and C. medinalis. Finally, in field trials, III-10 demonstrates better control efficiency against Chilo suppressalis compared to pyridalyl. Overall, our findings suggest that the modification of the middle alkyl chain of pyridalyl may be a promising approach for developing insecticides with improved efficacy.

Analysis of Antioxidant Constituents of Filtering Infusions from Oak (Quercus sideroxyla Bonpl. and Quercus eduardii Trel.) and Yerbaniz (Tagetes lucida (Sweet) Voss) as Monoamine Oxidase Inhibitors.

The antioxidant constituents of ancestral products with ethnobotanical backgrounds are candidates for the study of filtering infusions to aid in pharmacotherapies focused on the treatment of depression and anxiety. Monoamine oxidase A (MAO-A) is an enzyme that regulates the metabolic breakdown of serotonin and noradrenaline in the nervous system. The goal of this study was to evaluate in vitro and in silico the effect of antioxidant constituents of filtering infusions from yerbaniz (Tagetes lucida (Sweet) Voss) and oak (Quercus sideroxyla Bonpl. and Quercus eduardii Trel.) as monoamine oxidase inhibitors. Materials were dried, ground, and mixed according to a simplex-centroid mixture design for obtaining infusions. Differential analysis of the phenolic constituent's ratio in the different infusions indicates that among the main compounds contributing to MAO-A inhibition are the gallic, chlorogenic, quinic, and shikimic acids, quercetin glucuronide and some glycosylated derivatives of ellagic acid and ellagic acid methyl ether. Infusions of Q. sideroxyla Bonpl. leaves, because of their content (99.45 ± 5.17 µg/mg) and synergy between these constituents for MAO-A inhibition (52.82 ± 3.20%), have the potential to treat depression and anxiety. Therefore, future studies with pharmacological approaches are needed to validate them as therapeutic agents with applications in mental health care.

Synthesis and Determination of Anticancer Activity of Dicobalt Hexacarbonyl 2'-Deoxy-5-alkynylfuropyrimidines.

Dicobalt hexacarbonyl 5-alkynyl furopyrimidine nucleoside analogs, with 4-methylphenyl (p-tolyl) and 4-pentylphenyl substituents attached at the C-6 base position, designed in the form of ribose acetyl esters, were synthesized (42-96%). Attached at the C-5 position were propargyl alcohol, its methyl ether and acetate derivatives, butynol, and the 4-methylphenyl- (p-tolyl) and 4-pentylphenyl-substituted alkynyl groups, which were coordinated to a dicobalt hexacarbonyl unit. The structure of 5-(3-acetoxyprop-1-yn-1-yl)-6-p-tolyl-2'-deoxyribofuranosyl-furo[2,3-d]pyrimidin-2-one was determined by X-ray crystallography. Density functional theory calculations performed on the corresponding derivative yielded geometric parameters for the dicobalt hexacarbonyl adduct of this ligand. The cytotoxic activity of each of dicobalt modified nucleosides on cancer cells of different phenotypes was determined in vitro. The investigated compounds showed antiproliferative effects with median inhibitory concentration (IC50) values in the ranges of 14-90 and 9-50 μM for HeLa and K562 cells, respectively. The formation of reactive oxygen species in the presence of modified nucleosides was determined in K562 cells. The results indicate that the mechanism of action for the studied compounds may be related to the induction of oxidative stress.

Ether Derivatives of Naringenin and Their Oximes as Factors Modulating Bacterial Adhesion.

Because of the close connection between adhesion and many vital cellular functions, the search for new compounds modulating the adhesion of bacteria belonging to the intestinal microbiota is a great challenge and a clinical need. Based on our previous studies, we discovered that O-lkyl naringenin derivatives and their oximes exhibit antimicrobial activity against antibiotic-resistant pathogens. The current study was aimed at determining the modulatory effect of these compounds on the adhesion of selected representatives of the intestinal microbiota: Escherichia coli, a commensal representative of the intestinal microbiota, and Enterococcus faecalis, a bacterium that naturally colonizes the intestines but has disease-promoting potential. To better reflect the variety of real-life scenarios, we performed these studies using two different intestinal cell lines: the physiologically functioning ("healthy") 3T3-L1 cell line and the disease-mimicking, cancerous HT-29 line. The study was performed in vitro under static and microfluidic conditions generated by the Bioflux system. We detected the modulatory effect of the tested O-alkyl naringenin derivatives on bacterial adhesion, which was dependent on the cell line studied and was more significant for E. coli than for E. faecalis. In addition, it was noticed that this activity was affected by the concentration of the tested compound and its structure (length of the carbon chain). In summary, O-alkyl naringenin derivatives and their oximes possess a promising modulatory effect on the adhesion of selected representatives of the intestinal microbiota.

Three-component reaction of tert-butyl nitrite with indoles and halides: A facile and efficient synthesis of oxime ether derivatives

A mild and efficient one-pot method has been developed for the synthesis of oxime ether derivatives with up to 85% yield by employing tert-butyl nitrite (TBN) as nitrogen source, which occurs under room temperature and exhibits wide substrate scope. The single electron transfer mechanism and the cascade reactions approach have been confirmed.

Quantitative genetic parameters of heartwood and its chemical traits in a black pine (Pinus nigra J.F.Arnold) clonal seed orchard established in Greece

Background: Black pine (Pinus nigra J.F.Arnold) is one of the most productive conifers species for timber production in southern Europe, the Mediterranean region and Greece. Recently, the interest for its heartwood extractives content due to their medicinal properties has been renewed. Black pine can be used to produce high added value products, such as bioactive compounds produced from wood and wood waste materials. Methods: Quantitative genetic parameters were estimated for heartwood chemical traits and heartwood percentage in a 44-year-old Pinus nigra clonal seed orchard, established in Peloponnese, Greece. Results: Significant variation was found among clones and among provenances for all studied traits. Heritability on a clone mean basis was extremely high for total acetone extractives, total resin acids as for all resin acids (≥0.85), except levopimaric acid (0.47) and very high for total stilbenes, pinosylvins as for dehydroabietic acid and heartwood percentage (0.69-0.79). On an individual basis, the genetic control was moderate to high (0.53-0.62) for total acetone extractives, total resin acids as for most of resin acids (≥0.85) with dehydroabietic acid presenting low value (0.39) while levopimaric acid very low (0.15). Total stilbenes, pinosylvins and its ether derivatives as heartwood percentage exhibited low values of heritability on individual basis (0.31-0.43). The phenotypic correlation (rp) between total acetone extracts and total stilbenes was negatively weak (≤-0.173) and significant (p≤0.01) while the genetic correlation (rg) was moderate to strong (≤-0.502). The rp values between several pinosylvins were significantly (p≤0.01) moderate to strong (0.529-0.975) as were genetic correlations (0.583-0.975). Between the studied resin acids, both rp and rg values were mostly medium to strong (rp≥0.8 and rg≥0.7) and significant (p≤0.01) in the case of phenotypic correlations, with minor exceptions (levopimaric acid). Phenotypic and genetic correlations between heartwood percentage and its chemical traits were positive (being in most cases significant), except for dehydroabietic and levopimaric acid. Conclusions: The studied clones, comprising the clonal seed orchard, can be used in clonal forestry and subsequent breeding cycles, indicating high potential for advanced breeding, especially for heartwood extractives that are of high pharmaceutical and economic value.

In vitro activity and mechanism of cell death induction of cyanomethyl vinyl ethers derivatives against Trypanosoma cruzi

Chagas disease causes a problematic pathology that can lead to megacolon and heart disease, and can even cause the death of the patient. Current therapies for this disease are the same as they were 50 years ago, are not fully effective and have strong side effects. The lack of a safe and effective therapy makes it necessary to search for new, less toxic and totally effective compounds against this parasite. In this work, the antichagasic activity of 46 novel cyanomethyl vinyl ether derivatives was studied. In addition, to elucidate the type of cell death that these compounds produce in parasites, several events related to programmed cell death were studied. The results highlight four more selective compounds, E63, E64, E74 and E83, which also appear to trigger programmed cell death, and are therefore postulated as good candidates to use in future therapeutics for Chagas disease.

Pharmacological Properties of <i>Genista sagittalis</i> L. (Fabaceae) Grown in Turkey

The genus Genista L. (Family: Fabaceae) is a plant having several traditional uses for treating common ailments such as diabetes, ulcer, and respiratory diseases. In this current study, the composition of essential oil and the biological activities of Genista sagittalis L. (Fabaceae) from Kocaeli: Yuvacık Dam Basin have been studied. A total of fourteen components were identified in the essential oil. The identified compounds belonged to straight-chain alkane, aromatic ether, and terpenoid derivatives. The antibacterial activity analyses demonstrated that G. sagittalis flower extract only had low activity against P. mirabilis and P. aeruginosa with MICs 1 to 2 mg/mL, as the peduncle extract showed strong anti-QS activity at 1.3 mg/mL. To the best of our knowledge, the current work is the first to report the antimicrobial and anti-quorum sensing activity of G. sagittalis growing in Turkey. Double-stranded DNA binding affinity investigations of the flower and peduncle ethanol extracts indicate that there are interactions with double-stranded DNA and related binding constants (Kb) were found as 1.97×103±0.37 and 3.68×102±0.44 for the flower and peduncle extract, respectively.

Qualitative structure-activity relationships of aryl isoprenoid derivatives as biorational juvenoids - reweighing.

The online version contains supplementary material available at 10.1007/s42690-023-01025-3.

Practical Synthesis of Tenofovir Alafenamide Fumarate Inspired by New Retrosynthetic Disconnection Featuring a Novel Carbon–Phosphorus Bond Construction Methodology

Tenofovir alafenamide fumarate (TAF) is rising as a mainstay antiretroviral agent for the treatment of HIV and chronic HBV infections. A de novo practical synthesis of TAF circumventing tenofovir (PMPA) has been accomplished on a 7 g scale. This reimagined synthesis of TAF, inspired by a hitherto uncharted retrosynthetic disconnection, centers on the P-alkylation of silylated diphenyl phosphonate 10 (as acceptor) with methylthiomethyl (MTM) ether derivative 11 (as donor) in the presence of NIS/TfOH combination as a promoter to construct the strategic carbon–phosphorus bond. This PMPA-free synthesis of TAF not only removes the intrinsic drawbacks encountered by the PMPA-dependent commercial process but also is beneficial to the diversification of the synthetic portfolio of TAF. Furthermore, this type of P-alkylation reaction with defined stereochemistry could be deployed for the late-stage modification of druglike molecules and natural products to access valuable phosphonate derivatives.

Complexation mechanism of crown ethers with rubidium and cesium ions using density functional theory

The complexation mechanism of crown ether derivatives (18C6, 21C7, B18C6, B21C7) with metal ions (Li+, K+, Rb+, Cs+) has been studied. Structural optimization was performed at the level of M06-2X/def2SVP. The results show that M+ mainly interacts with oxygen atoms, and CO bonds become longer after complexation. The interactions belong to the electrostatic attractive effect. The electrophilic substitution activity of crown ethers can be improved by benzene ring substituents, while the electrophilic complexing reaction activity decreases. 21C7 has the lowest electrostatic potential minimum, which is −96.0 kcal·mol−1. The complex 21C7-Cs+ and 21C7-Rb+ are more stable than other 21C7 complexes. The binding energy and Gibbs free energy of 21C7-Cs+ are −66.6 and −66.0 kcal·mol−1, respectively. The results can provide theoretical guidance for the design of crown ethers using for the extraction of Rb+ and Cs+ from brines.

Nickel-Catalyzed Remote Asymmetric Hydroalkylation of Alkenyl Ethers to Access Ethers of Chiral Dialkyl Carbinols.

Site- and enantio-selective alkyl-alkyl bond formation is privileged in the retrosynthetic analysis due to the universality of sp3-hybridized carbon atoms in organic molecules. Herein, we report a nickel-catalyzed remote asymmetric hydroalkylation of alkenyl ethers via synchronous implementation of alkene isomerization and enantioselective C(sp3)-C(sp3) bond formation. Regression analysis of catalyst structure-activity relationships accelerates the rational ligand modification through modular regulation. This reaction has several advantages for synthesizing chiral dialkyl carbinols and their ether derivatives, including the broad substrate scope, good functional group tolerance, excellent regioselectivity (>20:1 regioisomeric ratio), and high enantioselectivity (up to 95% enantiomeric excess).

Electrophilic substitution reactivity prediction of crown ether derivatives

AbstractLithium is important for the world's economic development because it is the primary component of batteries. Crown ether derivatives are widely used for the separation and enrichment of lithium. The conformations of the designed crown ether were studied using molecular dynamics simulation. The electrophilic substitution reactivities of different conformations were analyzed by the conceptual density functional theory (CDFT) and the frontier molecular orbital theory (FMO). The analysis results show that the reactivity of the phenyl group can be increased by the π–π conjugation effect and bonded oxygen atoms. According to the reduced density gradient (RDG), the van der Waals interactions between the phenyl functional groups and methyl groups also benefit the reactivity. According to the global softness and nucleophilicity index, the reactivity of is the highest. The condensed Fukui function, condensed local nucleophilicity index, and condensed local softness show that the electrophilic substitution reactivity of is the highest. also has the largest HOMO orbital composition. The analysis results of CDFT and FMO are consistent with each other, which suggests that the Koopmans approximation is suitable for the reactivity analysis of crown ether derivatives.

Diaryl ether derivative inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells.

Papillary thyroid carcinoma contributes to about 80% of the total thyroid cancer cases. BRAFV600E is a frequently occurring mutation in PTCs. Although several BRAF inhibitors are available, many thyroid cancer patients acquire resistance to BRAF inhibitors. Therefore, new targets and drugs need to be identified as therapies. Ferroptosis is a recently discovered type of cell death, and inhibiting glutathione peroxidase 4 (GPX4) using small molecules was found to trigger ferroptosis. But it is unknown whether inhibiting GPX4 renders thyroid cancer cells susceptible to ferroptosis. To identify novel GPX4 inhibitors, we focused on our previously reported cohort of diaryl ether and dibenzoxepine molecules. In this study, we asked whether diaryl ether and dibenzoxepine derivatives trigger ferroptosis in thyroid cancer cells. To answer this question, we screened diaryl ether and dibenzoxepine derivatives in cell-based assays and performed mechanism of action studies. We found that a diaryl ether derivative, 16 decreased thyroid cell proliferation and triggered ferroptosis by inhibiting GPX4 expression levels. Molecular modeling and dynamics simulations showed that 16 binds to the active site of GPX4. Upon deciphering the mode of 16-induced ferroptosis, we found that 16 treatments decrease mitochondrial polarization and reduce mitochondrial respiration similar to a ferroptosis inducer, RSL3. We conclude that the diaryl ether derivative, 16 inhibits GPX4 expression levels to induce ferroptosis in thyroid cancer cells. Based on our observations, we suggest that 16 can be lead-optimized and developed as a ferroptosis-inducing agent to treat thyroid cancers.

Amentoflavone inhibits hepatitis B virus infection via the suppression of preS1 binding to host cells.

Hepatitis B virus (HBV) is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Current therapeutic drugs for chronic HBV infection use IFN and nucleos(t)ide analogs; however, their efficacy is limited. Thus, there is an urgent need to develop new antivirals for HBV therapy. In this study, we identified a plant-derived polyphenolic bioflavonoid, amentoflavone, as a new anti-HBV compound. Amentoflavone treatment dose-dependently inhibited HBV infection in HBV-susceptible cells with HepG2-hNTCP-C4 and primary human hepatocyte PXB-cells. A mode-of-action study showed that amentoflavone inhibits the viral entry step, but not the viral internalization and early replication processes. Attachment of HBV particles as well as HBV preS1 peptide to HepG2-hNTCP-C4 cells was inhibited by amentoflavone. The transporter assay revealed that amentoflavone partly inhibits uptake of sodium taurocholate cotransporting polypeptide (NTCP)-mediated bile acid. Furthermore, effect of various amentoflavone analogs on HBs and HBe production from HBV-infected HepG2-hNTCP-C4 cells was examined. Robustaflavone exhibited comparable anti-HBV activity to that of amentoflavone and an amentoflavone-7,4', 4‴-trimethyl ether derivative (sciadopitysin) with moderate anti-HBV activity. Cupressuflavone or the monomeric flavonoid apigenin did not exhibit the antiviral activity. Amentoflavone and its structurally related biflavonoids may provide a potential drug scaffold in the design of a new anti-HBV drug inhibitor targeting NTCP.

Ring-Opening Cyclization (ROC) of Aziridines with Propargyl Alcohols: Synthesis of 3,4-Dihydro-2H-1,4-oxazines.

Activated aziridines react with propargyl alcohols in the presence of Zn(OTf)2 as the Lewis acid catalyst following an SN2-type ring-opening mechanism to furnish the corresponding amino ether derivatives. Those amino ethers further undergo intramolecular hydroamination via 6-exo-dig cyclization in the presence of Zn(OTf)2 as the catalyst and tetrabutylammonium triflate salt as an additive under one-pot two-step reaction conditions. However, for nonracemic examples, ring-opening and cyclization steps were conducted under two-pot conditions. The reaction works well without any additional solvents. The final 3,4-dihydro-2H-1,4-oxazine products were obtained with 13 to 84% yield and 78 to 98% enantiomeric excess (for nonracemic examples).

Design, Synthesis, and Evaluation of Allosteric Effectors for Hemoglobin.

ConspectusSickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in hemoglobin (Hb), the protein in the red blood cell (RBC) responsible for the transport of oxygen (O2) throughout the body. The mutation leads to the expression of sickle cell hemoglobin (HbS). Both Hb and HbS exist in equilibrium between oxygenated and deoxygenated forms; however, deoxygenated HbS can polymerize to form long fibers which distort the shape of RBCs into the characteristic sickled shape. The misshapen RBCs can obstruct blood vessels and capillaries, resulting in a vaso-occlusive crisis. Vaso-occulsion deprives tissues and organs of O2 and can cause intense pain which often results in hospitalization. Chronic organ damage is a major cause of reduced life expectancy for SCD patients.Allosteric effectors are molecules which regulate protein function. HbS allosteric effectors can be used to decrease polymerization by stabilizing the oxygenated form of HbS, which leads to an increase in O2 uptake and a decrease in the sickling of RBCs. Allosteric effectors that have been evaluated for the treatment of SCD include vanillin, 5-hydroxymethyl furfural (5-HMF), and voxelotor, which was approved by the U.S. Food and Drug Administration (FDA) for the treatment of SCD in 2019. 5-HMF did not progress to phase III clinical trials since it suffered from rapid metabolic degradation. However, several derivatives of 5-HMF and vanillin have been synthesized and evaluated as potential candidates for SCD treatment. Derivatives of these compounds have shown promise, but their shortcomings, such as high levels of oxidative metabolism, have prevented them from progressing into marketable drugs. Our efforts have produced multiple 5-HMF derivatives which have been evaluated for their potential to treat SCD. Each derivative was evaluated for its ability to increase O2 affinity (i.e., P50, the partial pressure at which hemoglobin is 50% saturated with O2). The synthesized aryl ether derivatives were evaluated, and results suggest that compounds with multiple aromatic aldehydes may have enhanced biological properties. One such derivative, compound 5, which features two furan aldehyde rings, exhibited increased O2 affinity (P50 = 8.82 ± 1.87 mmHg) over that of unmodified Hb (P50 = 13.67 ± 0.22 mmHg). Future studies include obtaining crystal structures of the 5-HMF derivatives complexed with HbS to confirm the protein-allosteric effector interactions.

Cationic cascade cyclizations terminated by MOM ether derivatives of β-keto esters

It has been known for some time that cationic cascade cyclizations initiated by Lewis acid mediated opening of an epoxide can be trapped by reaction with a β-keto ester. The studies reported here show that the efficiency of these cyclizations can be improved through preparation of a MOM enol ether from the β-keto ester. Furthermore, in both geranyl and farnesyl derivatives the stereochemistry of the enol ether controls formation of the major product. In both series, the E-enol ether leads to a cyclic vinylogous carbonate incorporating the oxygen originating in the ketone in the ring system, while the Z-enol ether leads to a cyclic enone incorporating the oxygen originating in the ester carbonyl group. Upon treatment with catalytic HCl, a facile rearrangement converts the enone product to the vinylogous carbonate. Because these cyclizations faithfully extend the stereochemistry of the original epoxide into multiple stereocenters, they have the potential to afford significantly more complex structures from relatively simple starting materials.

A Comparison of the Antibacterial Efficacy of Carbohydrate Lipid-like (Thio)Ether, Sulfone, and Ester Derivatives against Paenibacillus larvae.

Paenibacillus larvae is the causative agent of American foulbrood (AFB), the most serious bacterial disease affecting developing honeybee larvae and pupas. In this study, a library of 24 (thio)glycosides, glycosyl sulfones, 6-O-esters, and ethers derived from d-mannose, d-glucose, and d-galactose having C10 or C12 alkyl chain were evaluated for their antibacterial efficacy against two P. larvae strains. The efficacy of the tested compounds determined as minimal inhibitory concentrations (MICs) varied greatly. Generally, dodecyl derivatives were found to be more potent than their decylated analogs. Thioglycosides were more efficient than glycosides and sulfones. The activity of the 6-O-ether derivatives was higher than that of their ester counterparts. Seven derivatives with dodecyl chain linked (thio)glycosidically or etherically at C-6 showed high efficacy against both P. larvae strains (MICs ranged from 12.5 μM to 50 μM). Their efficacies were similar or much higher than those of selected reference compounds known to be active against P. larvae-lauric acid, monolaurin, and honeybee larval food components, 10-hydroxy-2-decenoic acid, and sebacic acid (MICs ranged from 25 μM to 6400 μM). The high efficacies of these seven derivatives suggest that they could increase the anti-P. larvae activity of larval food and improve the resistance of larvae to AFB disease through their application to honeybee colonies.

Photoantibacterial Poly(vinyl)chloride Films Applying Curcumin Derivatives as Bio-Based Plasticizers and Photosensitizers.

Herein we describe the design of natural curcumin ester and ether derivatives and their application as potential bioplasticizers, to prepare photosensitive phthalate-free PVC-based materials. The preparation of PVC-based films incorporating several loadings of newly synthesized curcumin derivatives along with their standard solid-state characterization is also described. Remarkably, the plasticizing effect of the curcumin derivatives in the PVC material was found to be similar to that observed in previous PVC-phthalate materials. Finally, studies applying these new materials in the photoinactivation of S. aureus planktonic cultures revealed a strong structure/activity correlation, with the photosensitive materials reaching up to 6 log CFU reduction at low irradiation intensities.