Symmetrical Triazine Research Articles

Solid Phase Synthesis, DFT Calculations, Molecular Docking, and Biological Studies of Symmetrical N 2,N 4,N 6-Trisubstituted-1,3,5-triazines.

A diversity-oriented, multicomponent convergent synthesis of symmetrical triazines through a one-pot protocol is presented in this research project. The assembly of trisubstituted triazines was initially carried out using easily available reagents through three different protocols, i.e., conventional, MW-assisted synthesis, and solid-supported MW-assisted synthesis using organic and inorganic support to carry out a comparative analysis as to which procedure best corresponds to a greener synthesis protocol. The compounds formed were characterized for structure elucidation and subjected to in vitro anticancer and antibacterial screening. Additionally, computational studies, such as DFT calculations and molecular docking analyses, were conducted.

Terbutryn causes developmental toxicity in zebrafish (Danio rerio) via apoptosis and major organ malformation in the early stages of embryogenesis

Terbutryn (2-(ethylamino)-4-(tert-butylamino)-6-(methylthio)-1,3,5-triazine) is a substituted symmetrical triazine herbicide used in agricultural fields to prevent undesired vegetation growth by inhibiting photosynthesis in target weeds. Although terbutryn has various benefits, long-term exposure, misuse, or abuse of terbutryn may cause non-target toxicity and severe ecosystem pollution. To provide a detailed description of the embryonic developmental toxicity of terbutryn, zebrafish (Danio rerio) were exposed to 2, 4, and 6 mg/L of terbutryn and the morphological changes, pathological abnormalities, and developmental endpoints were assessed relative to that of a solvent control. The results showed that terbutryn induces a loss of survivability, reduction in body and eye size, and edema in the yolk sac. Through fluorescence microscopy, blood vessels, motor neurons, and liver development were investigated using transgenic zebrafish models based on fluorescently tagged genes (fllk1:eGFP, olig2:dsRed, and L-fabp:dsRed). Furthermore, cell death by apoptosis in zebrafish caused by terbutryn exposure was evaluated via acridine orange staining, which is a selective fluorescent staining agent. To support the preceding results, gene expression alterations caused by terbutryn exposure in zebrafish larvae were assessed. The overall results indicate that exposure to terbutryn induces apoptosis and disrupts organ development. These embryonic developmental toxicity results suggest that terbutryn should be applied in the right areas at the appropriate rates, concentrations, and quantities.

New Perspective on Comparative Chemometric and Molecular Modeling of Antifungal Activity and Herbicidal Potential of Alkyl and Cycloalkyl s-Triazine Derivatives

The contamination of the environment by pesticides is becoming a burning issue in many countries in the World. Development, design, and synthesis of new eco-friendly pesticides and modification of existing ones in order to improve their efficacy with the lowest impact on the environment are two main future possibilities in crop protection and the provision of sufficient food for the growing world population. The present study is focused on the comparative analysis of a series of eight symmetrical triazine derivatives, as potential herbicide candidates with acyclic (alkyl) and cyclic (cycloalkyl) substituents, in terms of their antifungal activity towards Aspergillus flavus as an opportunistic fungal pathogenic microorganism responsible for frequent contaminations of crops with aflatoxin, and in terms of their potential application as herbicides in maize, common wheat, barley, and rice crops. The applied methods include the chemometric pattern recognition method (hierarchical cluster analysis), experimental microbiological analysis of antifungal activity (agar well-diffusion method), and molecular docking of the triazines in the corresponding enzymes. The main findings of the conducted study indicate the significant antifungal activity of the studied triazine derivatives towards A. flavus, particularly the compounds with acyclic substituents; five out of eight studied triazines could be applied as systematic herbicides, while the other three triazines could be used as contact herbicides; the compounds with acyclic substituents could be more suitable for application for various crops protection than triazines with cyclic substituents.

Green analytical method based on salt assisted graphene oxide dispersive solid phase extraction of symmetrical triazine herbicides in environmental water samples for liquid chromatographic determination

ABSTRACT Graphene oxide (GO) was used as sorbent in dispersive solid phase extraction (DSPE) to enrich and extract some triazine herbicides from environmental water samples. It can form dispersed colloids in aqueous phase and provides rich functional groups for the formation of hydrogen bonding or π–π electrostatic interaction with benzene ring organic compounds containing oxygen and nitrogen functional groups. GO was synthesised by modified Hummers method and characterised with Fourier transform infrared (FT-IR) spectroscopy. As complete collection of GO after adsorption process is difficult task, in this established salt-assisted (SA)-GO-DSPE method, it was found to be aggregated and centrifuged in the presence of NaCl. The optimum value for main parameters that influenced extraction efficiency were investigated. Under the optimised conditions, low limits of detection (LODs) (0.12–0.80 ng mL −1), limits of quantification (LOQ) (0.4–2.68 ng mL −1), and good extraction recoveries (69.06–95.53%) were obtained for simultaneous extraction of simazine (SIZ), atrazine (ATZ), propazine (PRZ)) and prometryn (PRN). The relative standard deviations (RSD) of intraday (n = 6) and interday (n = 9) precisions were 2.54 to 5.84% and 4.38 to 8.56%, respectively. At the end, the applicability of the method was evaluated and target analytes were not detected in real samples. The proposed method is environment friendly and promising for trace analysis of pesticides including the target herbicides in environmental water samples.

Linear quantitative structure-ecotoxicity relationship modeling of a series of symmetrical triazine derivatives based on physicochemical parameters

The present study reports the Quantitative Structure-Ecotoxicity Relationship (QSER) analysis of a series of 21 1,3,5-triazine derivatives based on multiple-linear regression (MLR) method. The ecotoxicity data were estimated by using in silico approach and included the following parameters: acute algae toxicity (AAT), acute daphnia toxicity (ADT), Daphnia Magna LC50 48h/EPA (DMepa) and Daphnia Magna LC50 48h/DEMETRA (DMdemetra). The ecotoxicity data were correlated with molecular descriptors selected by using the stepwise selection method. The considered molecular descriptors are lipophilicity descriptors (CrippenLogP, ALogp2), Autocorrelation Descriptor Mass (ATSm1, ATSm2, ATSm3, ATSm4), Autocorrelation Descriptor Charge (ATSc2), minimum E-states for (strong) hydrogen bond acceptors (minHBa), maximum E-states for (strong) hydrogen bond acceptors (maxHBa), second kappa shape index (Kier2), maximum atom-type E-State: ?:N:? (maxaaN), sum of path lengths starting from nitrogens (WTPT-5) and McGowan characteristic volume (McGowan_Volume). The modeling resulted in four statistically valid MLR models. The models were validated by the internal and external validation approaches. The external validation confirmed high predictive ability of the established MLRs.

Practical One-Pot Synthesis of 4,6-Bis(hetero)aryl- and 4-(Hetero) aryl-6-methyl-substituted 1,3,5-Triazin-2-amines

AbstractTwo series of 4,6-disubstituted 1,3,5-triazin-2-amines were prepared by cesium carbonate-promoted cotrimerization of aromatic nitriles with guanidine and the reaction of (hetero)aryl nitriles with N-acetylguanidine. The first series of 4,6-bis(hetero)aryl-1,3,5-triazin-2-amines was synthesized in yields of 56–85% by adapting a traditional approach that starts from readily available substrates but requires strong and hard-to-handle bases as well as presents serious scope limitations. In this line, the method developed here used a mild base and overcame the scope limitation for p-substituted benzonitrile with electron-releasing group. The second series of 4-(hetero)aryl-6-methyl-1,3,5-triazin-2-amines comprises unsymmetrically substituted symmetrical triazines, which were synthesized in yields of 58–75%. In summary, this work highlighted a synthetic method, which tolerates broad range of substrates, including o- and p-substituted benzonitriles as well as heteroaromatic nitriles.

High-Symmetry Co/Ni Triazine Polycarboxylate Diverse Frameworks Constructed by Mx(COO)y Building Blocks: Characterization and Catalytic Performance Evaluation of p-Nitrophenol.

Three new triazine compounds [Co1.5(H3TDPAT)(H2O)3]·6H2O (1), [Co2(TCPT)(μ2-H2O)2]·OH (2), and [Ni3(TCPT)]·3OH (3) were designed and synthesized via the reaction of the symmetrical triazine ligand connected by C-N-C and C-O-C bonds with triazine poly(carboxylic acid)s ligands as the side arms: H6TDPAT (H6TDPAT = 2,4,6-tris(3,5-dicarboxylphenylamino)-1,3,5-triazine) and H3TCPT (H3TCPT = 2,4,6-tris(4-carboxyphenoxy)-1,3,5-triazine) as well as the corresponding metal salts under the solvothermal condition. Three triazine polycarboxylate frameworks were characterized by elemental analysis, infrared spectroscopy, ultraviolet spectroscopy, thermogravimetric analysis, X-ray powder diffraction, and solid fluorescent spectra in detail. The structural analysis results showed that the three-dimensional porous cage framework of compound 1 was constructed by three different polyhedral cages connected with [Co(COO)4(H2O)2] building blocks. One of the compounds, 2, is formed by twin propeller Co2(μ2-H2O)(COO)3 building blocks connecting two-dimensional layers and the intermolecular π-π interactions involved the triazine rings between the layers. While the structure of compound 3 is similar to that of 2, assembly is by Ni(COO)3 building blocks and adjacent layers of the face-to-face π-π interaction between the triazine rings. In order to explore functional properties, the catalytic reduction of p-nitrophenol (PNP) of compounds 1-3 was investigated. They exhibit excellent catalytic activity of more than 95% for reduction of PNP with a dose of 2.5 mg of the compounds.

Stable-Isotope Dilution GC–MS Measurement of Metformin in Human Serum and Urine after Derivatization with Pentafluoropropionic Anhydride and Its Application in Becker Muscular Dystrophy Patients Administered with Metformin, l-Citrulline, or Their Combination

Metformin (N,N-dimethylguanylguanidine) is one of the most prescribed drugs with pleiotropic, exerted in part by not fully elucidated mechanisms of action. We developed and validated a gas chromatography–mass spectrometry (GC–MS) method for the quantitative analysis of metformin (metformin-d0) in 10-µL aliquots of human serum and urine using N,N-[dimethylo-2H6]guanylguanidine (metformin-d6) as the internal standard. The method involves evaporation of the samples to dryness, derivatization with pentafluoropropionic (PFP) anhydride in ethyl acetate (30 min, 65 °C), and extraction into toluene. The negative-ion chemical ionization GC–MS spectra of the PFP derivatives contain a single intense ion with mass-to-charge (m/z) ratios of m/z 383 for metformin-d0 and m/z 389 for metformin-d6. Our results suggest that all amine/imine groups of metformin-d0 and metformin-d6 are converted to their N,N,N-tripentafluoropropionyl derivatives, which cyclize to form a symmetric triazine derivative, of which the non-ring amine group is amidated. Quantification was performed by selected-ion monitoring (SIM) of m/z 383 and m/z 389. Upon validation, the method was applied to determine serum and urine metformin concentrations in 19 patients with Becker muscular dystrophy (BMD). Serum and urine samples were collected at baseline (Visit I), after six weeks of supplementation (Visit II) with metformin (3 × 500 mg/d; metformin group; n = 10) or l-citrulline (3 × 1500 mg/d; citrulline group; n = 9) followed by a six-week supplementation with 3 × 500 mg/d of metformin plus 3 × 1500 mg/d l-citrulline. At Visit I, the metformin concentration in the serum and urine was very low in both groups. The metformin concentrations in the serum and urine of the patients who first took metformin (MET group) were higher at Visit II and Visit III. The metformin concentration in the serum and urine samples of the patients who first took l-citrulline (CITR group) were higher at Visit III. The serum and urine concentrations of metformin were insignificantly lower in the CITR group at Visit III. The mean fractional excretion (FE) rate of metformin was 307% (Visit II) and 322% (Visit III) in the MET group, and 290% in the CITR group (Visit III). This observation suggests the accumulation of metformin in the kidney and its secretion in the urine. The GC–MS is suitable to measure reliably circulating and excretory metformin in clinical settings.

Isolation and characterization of cyromazine degrading Acinetobacter sp. ZX01 from a Chinese ginger cultivated soil.

Cyromazine, a symmetrical triazine insecticide, is used to control dipteran larvae in chicken manure by feeding to the poultry, flies on animals, and leafminers in vegetables. Its extensive use has resulted in the widespread contamination in the environment. In the current study, a cyromazine degrading bacterium (designated strain ZX01) was isolated and characterized from a Chinese ginger cultivated soil by selective enrichment culture method. On the basis of morphological, biochemical characteristics, and 16S rRNA gene sequence, this bacterium showed strong similarity to the Pseudomonadales members and was closely related to the Acinetobacter baumannii group. Spectrophotometric and HPLC analyses revealed that strain ZX01 degraded cyromazine and utilized it as the sole carbon source for its growth. This process hydrolyzes cyromazine to melamine. Strain ZX01 degraded most of the cyromazine in 60h. Besides, its substrate specificity against four symmetrical triazine herbicides, one triazinone herbicide, as well as 10 insecticides and its antibiotic sensitivity towards eight commercial antibiotics were also tested. At the concentration of 100µg/mL for 60h, it could effectively degrade a variety of different pesticides, including atrazine, prometon, simazine, prometryn, enitrothion, diazinon, cypermethrin, and acetamiprid, and the degradation was in the range of 71-87%. In particular, melamine, the main degradation product of cyromazine, was degraded by 47.3%. This microorganism was sensitive to chloramphenicol and tetracycline and intermediate to amoxicillin and trimethoprim. These results highlight that strain ZX01 can be used as a potential biological agent for the remediation of soil, water, or crop contaminated with cyromazine and other symmetrical triazine insecticides.

Изучение влияния детонационных наноалмазов и их конъюгатов с доксорубицином и диоксадэтом на функцию митохондрий

Targeted drug delivery is aimed at preventing drugs’ nonspecific distribution in different tissues. One of efficient ways for drug’s targeted delivery is using denonation nanodiamonds. These nanoparticles are an advantageous material for nanomedicine due to their low cost, biocompatibility, hardness and chemical stability. Majority of blood plasma proteins and blood cell surfaces are charged negatively. Therefore biocompatibility and long circulation lifetimes of carboxylated nanodiamonds can be partially attributed to their negative surface charge. The presence of different functional groups on nanodiamond surfaces enables their functionalization with a variety of therapeutic agents, including antitumour drugs. One of them is dioxadet, a derivative of symmetric triazine. It is becoming evident that mitochondria play crucial role in metastasis and chemoresistance of tumors, which makes them a very promising target for anticancer therapy. In particular, proton translocating F1Fo-ATPase/ATP synthase can be one of these targets. This enzyme is responsible for making the majority of ATP in the cell by oxidative phosphorylation. More than 300 natural and synthesized compounds are currently known to interact with or inhibit F1Fo, but a comparative study of their effects on energy metabolism has only recently started. In this work we estimated effects of the cytostatic drugs doxorubicin, dioxadet and their DND conjugates on the activity of F1Fo ATPase as well as on the membrane potential. Two model systems were employed: 1) E. coli F1Fo-ATPase reconstituted into phosphatidylcholine liposomes; 2) Pancreatic carcinoma cell line PANC1. It was found that the nanodiamonds and conjugates exhibited the same uncoupling effect, partially dissipating the proton gradient across the membrane of proteoliposomes containing F1Fo-ATPase. In addition, the nanodiamonds inhibited ATPase activity. In an experiment on the effect on the mitochondrial membrane potential (PANC 1 cell line), conjugates of nanodiamonds with doxorubicin demonstrated a more pronounced effect compared to doxorubicin, which may be due to a combination of the uncoupling effect of nanodiamonds and doxorubicin-dependent generation of reactive oxygen species. The data reported in this paper shed light on effect of the carboxylated nanodiamonds on the cellular bioenergetics. These findings are crucial for further development of nanodiamond-based targeted drug delivery systems, in particular decreasing their toxicity by selecting optimal strategies of nanodiamond synthesis as well as drug immobilization on their surfaces. The use of artificial models of natural membranes, along with cell cultures, is necessary for a deeper and more accurate understanding of the mechanism of action of cytostatics.

Synthesis and Characterisation of a Boron-Rich Symmetric Triazine Bearing a Hypoxia-Targeting Nitroimidazole Moiety

Boron Neutron Capture Therapy (BNCT) is a binary therapy that promises to be suitable in treating many non-curable cancers. To that, the discovery of new boron compounds able to accumulate selectively in the tumour tissue is still required. Hypoxia, a deficiency of oxygen in tumor tissue, is a great challenge in the conventional treatment of cancer, because hypoxic areas are resistant to conventional anticancer treatments. 2-Nitroimidazole derivatives are known to be hypoxia markers due to their enrichment by bioreduction in hypoxic cells. In the present work, 2-nitroimidazole was chosen as the starting point for the synthesis of a new boron-containing compound based on a 1,3,5-triazine skeleton. Two o-carborane moieties were inserted to achieve a high ratio of boron on the molecular weight, exploiting a short PEG spacer to enhance the polarity of the compound and outdistance the active part from the core. The compound showed no toxicity on normal human primary fibroblasts, while it showed noteworthy toxicity in multiple myeloma cells together with a consistent intracellular boron accumulation.

Study of the spectra of asymmetric triazines with growth-stimulating activity

Derivatives of nitrogen-containing heterocycles, in particular compounds of symmetric and asymmetric triazines, are widely used in agriculture as regulators of plant growth and development. Among the derivatives, the most well-known use of symmetric derivatives, however, they are difficult to biodegrade and accumulate in the soil, and as a result in the plants themselves. Therefore, asymmetric triazines, which are easily decomposed in the environment, are more promising in practical terms. Currently, it is very important to use environmentally friendly plant growth and development regulators that do not contain impurities, so much attention is paid to the identification of synthesized compounds of asymmetric triazines with a substituent in position 5 using UV, IR and Mass spectroscopy.

A Comparison of Symmetrical and Asymmetrical Triazine Herbicides for Enhanced Degradation in Three Midwestern Soils

AbstractThe triazines are one of the most widely used herbicide classes ever developed and are critical for managing weed populations that have developed herbicide resistance. These herbicides are traditionally valued for their residual weed control in more than 50 crops. Scientific literature suggests that atrazine, and perhaps others-triazines, may no longer remain persistent in soils due to enhanced microbial degradation. Experiments examined the rate of degradation of atrazine and two other triazine herbicides, simazine and metribuzin, in both atrazine-adapted and non-history Corn Belt soils, with similar soils being used from each state as a comparison of potential triazine degradation. In three soils with no history of atrazine use, thet1/2of atrazine was at least four times greater than in three soils with a history of atrazine use. Simazine degradation in the same three sets of soils was 2.4 to 15 times more rapid in history soils than non-history soils. Metribuzin in history soils degraded at 0.6, 0.9, and 1.9 times the rate seen in the same three non-history soils. These results indicate enhanced degradation of the symmetrical triazine simazine, but not of the asymmetrical triazine metribuzin.

Adsorption of Triazine Derivatives with Humic Fraction-Immobilized Silica Gel in Hexane: A Mechanistic Consideration

A fraction of humic acid is collected under acidic conditions, then immobilized on silica gel and used as the adsorbent for various symmetrical triazine (s-triazine) derivatives in hexane. The enhanced hydrogen bonding between the analyte and humic fraction molecules, not the complexation interaction, is responsible for the adsorption observed in hexane, based on Fourier transform infrared (FTIR) spectroscopy results. The percentage of adsorption in hexane for all s-triazine derivatives reaches nearly 100% in 1 h, independent of the type, position, and size of the substituent on the aromatic nitrogen heterocyclic ring. Other factors leading to the variation of the percentage of adsorption include the type of liquid phase and the additive of acidic or basic origin present in the matrix.

Donor–acceptor ferrocenyl triazines: synthesis and properties

A series of star shaped donor–π–acceptor type symmetrical triazine was designed and synthesized by the Pd-catalysed Sonogshira cross coupling reaction. The ferrocenyl moiety with different spacer groups acts as donor and 1,3,5-triazine as acceptor. The photophysical results show intramolecular charge transfer from ferrocene to the 1,3,5-triazine unit. The cyclic voltammetric analysis reveals substantial donor–acceptor interaction. The triazines exhibit good thermal stability with high decomposition temperature.

Applicability of Liquid Chromatography with Time-of-Flight Mass Spectrometric Detection for Determination of Cyanuric Acid in Soil

Abstract. Cyanuric acid (2,4,6-trihydroxy-1,3,5-triazine, CA) is a highly polar and hydrophilic degrada-tion product of symmetric triazine herbicides, fairly stable under environmental conditions. We investi-gated the applicability of reversed-phase liquid chromatography coupled to time-of-flight mass spectrome-try (LC-ToF-MS) for qualitative and quantitative determination of CA in soils of different origin and pe-dological characteristics. CA was ultrasonically extracted from soils either with a mixture of acetone and n -hexane (volume ratio = 2:1) or with methanol and analysed on a LiChrospher 100 CN column with ψ(acetonitrile,water) = 50:50 as the mobile phase for isocratic elution. The efficiency and selectivity of LC-ToF-MS determination, using the electrospray ionisation in negative mode and selective monitoring of deprotonated CA molecule ( m/z 128), was evaluated with respect to injection volume, extracting solvent, and possible soil matrix interferences. The advantage of LC-ToF-MS over conventional HPLC with UV-diode array detection was the high ion detection selectivity minimising the interferences of coeluting spe-cies and the unambiguous identification of CA in soil extracts by accurate mass measurements of deproto-nated molecule. (doi: 10.5562/cca2109)

Application of reactive UV-absorbers for increasing protective properties of cellulose fabrics during standard laundering process

A number of water-soluble colourless fibre-reactive UV-absorbers derivatives of symmetrical triazine were used as additives during commercial laundering process. UV-protection factor (UPF) of such treated cotton tricot samples was measured. Changes in protection properties of modified textiles after repeated standard laundering process were determined. Carried-out experiments gave evidence of covalent bond formation between applied absorbers and cellulose fibre during standard washing process at 40 °C or 60 °C. Textiles modified by this method have provided UV-protective properties for prolonged time.

Synthesis of Novel Tri-Arm Star Shaped 1,3,5-triazine Hydrazones from 2,4,6-tris(4-acetylphenoxy)-1,3,5-triazine Core

A series of novel symmetric triazine hydrazones [N3C3(-OC6H4-p-C(CH3)=N-NH-C(O)-C6H4-p-X)3] (X = H, Br, Cl, F, OH, OCH3, CH3, NO2, NH2) were prepared in excellent yields by a three-fold condensation reaction of 2,4,6- tris(4-acetylphenoxy)-1,3,5-triazine with p-substituted benzoic acid hydrazides [NH2-NH-C(O)-C6H4-p-X]. The structures were confirmed by FT-IR, 1H, 13C, 2D-HMQC NMR and mass spectrometry (MALDI-TOF).

Biomonitoring of Human Exposure to Triazine Herbicides

Triazine herbicides are very common and only 0.1 % reach the target pests, while the rest moves into other environmental compartments. Their fate in the environment depends on their movement through the air, water, and soil and on the rate of their degradation or transformation. Triazine compounds may be transformed by water, microorganisms, and sunlight. Widespread use and persistence of triazine herbicides in soil has resulted in contamination of surface, drinking, and even rain water with parent compounds and degradation products, posing a risk to the general population.The metabolism and effects of triazine herbicides have been studied in experimental animals and in experiments in vitro. There are only a few studies of their metabolism and excretion in humans. Agricultural and manufacturing workers are exposed to triazines during application and production. Human exposure is monitored by determining parent compounds and their metabolites in urine. Due to the low concentrations of urinary metabolites in occupationally exposed persons, very sensitive analytical methods are required. This paper describes the structure and properties of symmetric triazine herbicides, their metabolism, and effects in humans and animals and the levels of these compounds in the urine of occupationally exposed persons.

High throughput quantitative analysis of melamine and triazines by MALDI-TOF MS

Quantitative and high throughput MALDI MS analysis of symmetrical triazines (s-triazines), and milk contaminated with melamine has been demonstrated. s-Triazines from a multi component aqueous test mixture, and melamine, a known adulterant in milk, were quantified at low parts-per-million (ppm) level using 2,5-dihydroxybenzoic acid (2,5-DHB) as a matrix. Mass spectral peak intensity ratios of the analyte and a suitable internal standard were used for the quantitation. Limit of detection at 20 ‘parts-per-billion’ (nano molar concentration) has been achieved for the s-triazines from the aqueous mixture. Quantitation from MALDI MS peak intensities was validated using LC-PDA and LC-ESI-MS analysis using both spectral peak intensities and areas under the chromatographic curves. Excellent linearity in low ppm concentrations along with good precision and accuracy, all of which were comparable to LC-ESI-MS data, were obtained with the advantage of rapid analysis.