Search Results (16)

Motile cilia play essential roles in various physiological processes including fluid flow generation and sperm motility. In this study, we identified 1,3-diphenyl-6-(4-phenylpiperazin-1-yl)benzo[e][1,2,4]triazin-7(1H)-one as a potent and reversible modulator of ciliary function using the Xenopus laevis model. This benzotriazinone derivative inhibits ciliary-driven fluid flow by inducing cilia detachment without causing toxicity in developing embryos. Unlike traditional deciliation agents that rely on calcium signaling, this compound induces cilia loss through a shear stress-driven mechanism at the transition zone, without disrupting tissue morphology or the apical actin network. Importantly, it also induces flagellar loss and impairs sperm motility at picomolar concentrations. Our findings highlight the potential of this 6-(4-phenylpiperazin-1-yl)-substituted benzotriazinone as a non-hormonal male contraceptive and underscore a novel mechanism of cilia modulation that may have broader implications for the treatment of cilia-related disorders. Full article

The thermal characterisation and toxicity profile of a class of disubstituted heterofused triazinones were revealed in this article for the first time. The thermal behaviour of molecules 1–12 was investigated by means of TG and DSC analyses performed in an air atmosphere and by the coupled TG/FTIR technique in a nitrogen atmosphere. The heating atmosphere affects both the stability of compounds and the degradation mechanism. A two-step degradation occurs in air, while a one-step degradation takes place in nitrogen, both preceded by a melting process. Compound 3 shows the highest thermal stability, while molecule 10—the lowest. The thermal decomposition of the studied heterocyclic molecules begins with the degradation of the bicyclic system, resulting in the formation of volatile gaseous products such as ammonia/hydrazine, hydrogen cyanide, carbon dioxide, and isocyanates. In the further stage, mainly aromatic compounds are released, and their chemical composition depends on the presence and type of substituents at the phenyl and benzyl moieties. In addition, the toxicity profiles of molecules were assessed in the animal (zebrafish) and cellular (erythrocytes) models, and the antihaemolytic activity was evaluated in the AAPH- and H₂O₂-induced haemolysis inhibition assays. It was found that all the tested compounds are safe for the developing zebrafish and red blood cells, and they are able to effectively protect erythrocytes from oxidative damage. These favourable properties make them promising drug candidates suitable for further in vivo studies. Full article

The exploration of heterocyclic compounds and their fused analogs, featuring key pharmacophore fragments like pyridine, thiophene, pyrimidine, and triazine rings, is pivotal in medicinal chemistry. These compounds possess a wide array of biological activities, making them an intriguing area of study. The quest for new neurotropic drugs among derivatives of these heterocycles with pharmacophore groups remains a significant research challenge. The aim of this research work was to develop a synthesis method for new heterocyclic compounds, evaluate their neurotropic and neuroprotective activities, study histological changes, and perform docking analysis. Classical organic synthesis methods were used in the creation of novel heterocyclic systems containing pharmacophore rings. To evaluate the neurotropic activity of these synthesized compounds, a range of biological assays were employed. Docking analysis was conducted using various software packages and methodologies. The neuroprotective activity of compound 13 was tested in seizures with and without pentylenetetrazole (PTZ) administration. Histopathological examinations were performed in different experimental groups in the hippocampus and the entorhinal cortex. As a result of chemical reactions, 16 new, tetra- and pentacyclic heterocyclic compounds were obtained. The biologically studied compounds exhibited protection against PTZ seizures as well as some psychotropic effects. The biological assays evidenced that 13 of the 16 studied compounds showed a high anticonvulsant activity by antagonism with PTZ. The toxicity of the compounds was low. According to the results of the study of psychotropic activity, it was found that the selected compounds have a sedative effect, except compound 13, which exhibited activating behavior and antianxiety effects (especially compound 13). The studied compounds exhibited antidepressant effects, especially compound 13, which is similar to diazepam. Histopathological examination showed that compound 13 produced moderate changes in the brain and exhibited neuroprotective effects in the entorhinal cortex against PTZ-induced damage, reducing gliosis and neuronal loss. Docking studies revealed that out of 16 compounds, 3 compounds bound to the γ-aminobutyric acid type A (GABA_A) receptor. Thus, the selected compounds demonstrated anticonvulsant, sedative, and activating behavior, and at the same time exhibited antianxiety and antidepressant effects. Compound 13 bound to the GABA_A receptor and exhibited antianxiety, antidepressant, and neuroprotective effects in the entorhinal cortex against PTZ-induced changes. Full article

In this article, for the first time, TG-DSC and TG-FTIR investigations of potential pharmaceutics, i.e., analgesic and anticancer active annelated triazinones (1–9) have been presented. The thermal behaviour of these molecules was established in oxidative and inert conditions. The solid–liquid phase transition for each compound (1–9) was documented by one sharp DSC peak confirming the high purity of each sample studied. All the molecules were characterised in terms of calorimetric changes and mass changes during their heating. They revealed high thermal stability in oxidative and inert conditions. The observed tendency in thermal stability changes in relation to a substituent present at the phenyl moiety was found to be similar in air and nitrogen. It was confirmed that annelated triazinones 1–9 were stable up to a temperature range of 241–296 °C in air, and their decomposition process proceeded in two stages under oxidative conditions. In addition, it was established that their thermal stability in air decreased in the following order of R at the phenyl moiety: 4-Cl > 3,4-Cl₂ > H > 3-Cl > 4-CH₃ > 2-CH₃ > 3-CH₃ > 2-Cl > 2-OCH₃. The volatile decomposition products of the investigated molecules were proposed by comparing the FTIR spectra collected during their thermogravimetric analysis in nitrogen with the spectra from the database of reference compounds. None of annelated triazinones 1–9 underwent any polymorphic transformation during thermal studies. All the compounds proved to be safe for erythrocytes. In turn, molecules 3, 6, and 9 protected red blood cells from oxidative damage, and therefore may be helpful in the prevention of free radical-mediated diseases. Full article

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium acetate. The reaction of oxazolones with phenylhydrazine, in acetic acid and sodium acetate, yielded the corresponding 1,2,4-triazin-6(5H)-ones. The structures of the compounds were confirmed using spectral (FT-IR, ¹H-NMR, ¹³C-NMR, MS) and elemental analysis. The toxicity of the compounds was evaluated on Daphnia magna Straus crustaceans and on the budding yeast Saccharomyces cerevisiae. The results indicate that both the heterocyclic nucleus and halogen atoms significantly influenced the toxicity against D. magna, with the oxazolones being less toxic than triazinones. The halogen-free oxazolone had the lowest toxicity, and the fluorine-containing triazinone exhibited the highest toxicity. The compounds showed low toxicity against yeast cells, apparently due to the activity of plasma membrane multidrug transporters Pdr5 and Snq2. The predictive analyses indicated an antiproliferative effect as the most probable biological action. The PASS prediction and CHEMBL similarity studies show evidence that the compounds could inhibit certain relevant oncological protein kinases. These results correlated with toxicity assays suggest that halogen-free oxazolone could be a good candidate for future anticancer investigations. Full article

The synthesis of two series of monocyclic and bicyclic trifluoromethylated 4,5-dihydro-1,2,4-triazin-6(1H)-one derivatives based on (3+3)-annulation of methyl esters derived from natural α-amino acids with in situ generated trifluoroacetonitrile imines has been described. The devised protocol is characterized by a wide scope, easily accessible substrates, remarkable functional group tolerance, and high chemical yield. In reactions with chiral starting materials, no racemization at the stereogenic centers was observed and the respective enantiomerically pure products were obtained. Selected functional group interconversions carried out under catalytic hydrogenation and mild PTC oxidation conditions were also demonstrated. Full article

Metribuzin is a pre- and post-emergence triazinone herbicide used in a variety of crops. This herbicide is degraded in the environment into three major metabolites that have high water solubility, high to very high soil mobility, and low to moderate persistence in soil. This paper describes the development of an analytical method based on ultrasound-assisted extraction and GC-MS/MS determination for the determination metribuzin and its main metabolites in soil and plants. The developed method provided good recoveries for all compounds in soil and plants (from 73 to 121%). The quantitation limits obtained from plants (2.6 to 18 µg/kg) allow determining the presence of these compounds at trace levels. To evaluate the applicability of the developed methods, bean plants were grown in plastic pots with soil treated with metribuzin and collected after 23 days. At the end of the assay, only 11% of the initial concentration of metribuzin remained in soil. Metribuzin and its three metabolites were detected in plants, desamino-diketo-metribuzin is the most abundant metabolite. It is expected that the application of these methods can provide more data to monitor metribuzin residues due to herbicide treatments. Full article

A group of novel trimethoxyphenyl (TMP)-based analogues were synthesized by varying the azalactone ring of 2-(3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxybenzylidene)oxazolone 1 and characterized using NMR spectral data as well as elemental microanalyses. All synthesized compounds were screened for their cytotoxic activity utilizing the hepatocellular carcinoma (HepG2) cell line. Compounds 9, 10 and 11 exhibited good cytotoxic potency with IC₅₀ values ranging from 1.38 to 3.21 μM compared to podophyllotoxin (podo) as a reference compound. In addition, compounds 9, 10 and 11 exhibited potent inhibition of β-tubulin polymerization. DNA flow cytometry analysis of compound 9 shows cell cycle disturbance at the G2/M phase and a significant increase in Annexin-V-positive cells compared with the untreated control. Compound 9 was further studied regarding its apoptotic potential in HepG2 cells; it decreased the level of MMP and Bcl-2 as well as boosted the level of p53 and Bax compared with the control HepG2 cells. Full article

New furan-based derivatives have been, designed, synthesized, and evaluated for their cytotoxic and tubulin polymerization inhibitory activities. DNA flow cytometric study of pyridine carbohydrazide 4 and N-phenyl triazinone 7 demonstrated G₂/M phase cell cycle disruptions. Accumulation of cells in the pre-G1 phase and positive annexin V/PI staining, which may be caused by degeneration or fragmentation of the genetic components, suggested that cell death occurs via an apoptotic cascade. Furthermore, compounds 4 and 7 had a strong pro-apoptotic impact through inducing the intrinsic mitochondrial mechanism of apoptosis. This mechanistic route was verified by an ELISA experiment that indicated a considerable rise in the levels of p53 and Bax and a drop in the level of Bcl-2 when compared with the control. Full article

In this paper, we propose the first analytical procedure—using a screen-printed carbon electrode modified with carbon nanofibers (SPCE/CNFs)—for the detection and quantitative determination of an electroactive disubstituted fused triazinone, namely 4-Cl-PIMT, which is a promising anticancer drug candidate. The electrochemical performances of the sensor were investigated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and square-wave adsorptive stripping voltammetry (SWAdSV). The presence of carbon nanofibers on the sensor surface caused a decrease in charge-transfer resistance and an increase in the active surface compared to the bare SPCE. Under the optimised experimental conditions, the proposed voltammetric procedure possesses a good linear response for the determination of 4-Cl-PIMT in the two linear ranges of 0.5–10 nM and 10–100 nM. The low limits of detection and quantification were calculated at 0.099 and 0.33 nM, respectively. In addition, the sensor displays high reproducibility and repeatability, as well as good selectivity. The selectivity was improved through the use of a flow system and a short accumulation time. The SWAdSV procedure with SPCE/CNFs was applied to determine 4-Cl-PIMT in human serum samples. The SWAdSV results were compared to those obtained by the ultra-high-performance liquid chromatography coupled with electrospray ionization/single-quadrupole mass spectrometry (UHPLC-ESI-MS) method. Full article

Pesticides are a large and heterogenous group of chemicals with a complex geographic distribution in the environment. The purpose of this study was to explore the geographic distribution of pesticides in Danish drinking water and identify potential patterns in the grouping of pesticides. Our data included 899,169 analyses of 167 pesticides and metabolites, of which 55 were identified above the detection limit. Pesticide patterns were defined by (1) pesticide groups based on chemical structure and pesticide–metabolite relations and (2) an exploratory factor analysis identifying underlying patterns of related pesticides within waterworks. The geographic distribution was evaluated by mapping the pesticide categories for groups and factor components, namely those detected, quantified, above quality standards, and not analysed. We identified five and seven factor components for the periods 2002–2011 and 2012–2018, respectively. In total, 16 pesticide groups were identified, of which six were representative in space and time with regards to the number of waterworks and analyses, namely benzothiazinone, benzonitriles, organophosphates, phenoxy herbicides, triazines, and triazinones. Pesticide mapping identified areas where multiple pesticides were detected, indicating areas with a higher pesticide burden. The results contribute to a better understanding of the pesticide pattern in Danish drinking water and may contribute to exposure assessments for future epidemiological studies. Full article

Potato producers in the Atlantic Canadian provinces of New Brunswick (NB) and Prince Edward Island (PE) rely on the photosystem II-inhibiting herbicide metribuzin for weed management. Recently, potato producers in the region have reported unacceptable common lambsquarters control following an application of metribuzin. Tissue and seed samples were collected from escaped common lambsquarters populations from across the potato producing regions of NB and PE and screened for the Ser264Gly mutation in psbA. Overall, 46% of sampled populations possessed the Ser264Gly mutation across the region. Cross-resistance testing to atrazine, metribuzin and linuron confirmed populations with the Ser264Gly were resistant to triazines and triazinones but remained susceptible to linuron. Dose response analysis determined a moderate level of resistance to metribuzin in common lambsquarters which would not be controlled in producers fields. A field experiment was conducted in Fredericton, NB and Harrington, PE, to determine if currently registered and unregistered products and tank-mixes would control PSII-inhibitor-resistant common lambsquarters in potato. All evaluated products, with the exception of S-metolachlor, provided control equivalent to the weed-free check without compromising potato yield or quality. This study demonstrates that PSII-inhibitor-resistant common lambsquarters are found in Atlantic Canadian potato production systems, but can be controlled with currently registered herbicides and rates with alternative modes of action. Full article

A series of novel 7-oxo-7H-thiazolo[3,2-b]-1,2,4-triazine-2-carboxylic acid derivatives was synthesized in good yields by a multi-step procedure that included the generation of the S-alkylated derivatives from 6-substituted arylmethyl-3-mercapto-1,2,4-triazin-5-ones with ethyl 2-chloroacetoacetate, intramolecular cyclization with microwave irradiation, hydrolysis and amidation. All of the target compounds were fully characterized through ¹H-NMR, ¹³C-NMR and HRMS spectra. The intramolecular cyclization occurred regioselectively at the N2-position of 1,2,4-triazine ring, which was confirmed by compound 3e using single-crystal X-ray diffraction analysis. The antibacterial and antitubercular activities of the target compounds were evaluated. Compared with Ciprofloxacin and Rifampicin, compounds 5d, 5f and 5g containing the terminal amide fragment exhibited broad spectrum antibacterial activity, and carboxylic acid derivatives or its corresponding ethyl esters had less effect on antibacterial properties. The most potent compound 5f also displayed excellent in vitro antitubercular activity against Mycobacterium smegmatis (minimum inhibitory concentration (MIC) = 50 μg/mL) and better growth inhibition activity of leucyl-tRNA synthetase (78.24 ± 4.05% at 15 μg/mL). Full article

A novel series of 7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one 6a–h, were easily prepared via reactions of novel 2-hydrazinyl-4,4-diphenyl-1H-imidazol-5(4H)-one (2) with hydrazonoyl halides 3a–h. In addition, we also examined the reaction of compound 2 with commercially available active methylene compounds to afford new pyrazoles containing an imidazolone moiety, expected to be biologically active. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, ¹H-NMR and mass spectral data. The antifungal and antibacterial activities of the newly synthesized compounds were evaluated. Full article

A series of S-glycosyl and S-alkyl derivatives of 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (1) were synthesized using different halo compounds such as preacetylated sugar bromide, 4-bromobutylacetate, 2-acetoxyethoxy-methyl bromide, 3-chloropropanol, 1,3-dichloro-2-propanol, epichlorohydrin, allyl bromide, propargyl bromide, phthalic and succinic acids in POCl₃. The structures of the synthesized compounds have been deduced from their elemental analysis and spectral (IR, ¹H-NMR, and ¹³C-NMR) data. Some of the synthesized compounds were screened as anticancer agents. Significant anticancer activities were observed in vitro for some members of the series, and compounds 4-Amino-3-(3-hydroxypropylthio)-6-(2-(2-thienyl)vinyl)-1,2,4-triazin-5(4H)-one (12) and 3-(4-Oxo-3-(2-(2-thienyl)vinyl)-4H-[1,3,4]thiadiazolo-[2,3-c][1,2,4]tr-iazin-7-yl)propanoic acid (18) are active cytotoxic agents against different cancer cell lines. Full article