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PubMed1985

Imidazo[1,5-d][1,2,4]triazines as potential antiasthma agents.

By using inhibition of histamine release from antigen-challenged, sensitized human basophils as a means of identifying a potentially prophylactic drug for the treatment of asthma, a series of substituted imidazo[1,5-d][1,2,4]triazines were found, which were active. These compounds were prepared by treating imidazolecarboxaldehydes with excess Grignard agent and then oxidizing the resulting alcohols to ketones with Jones reagent. Pyrolysis of a mixture of ketone and methyl carbazate at 200 degrees C in diphenyl ether produced the desired imidazo[1,5-d][1,2,4]triazines. Those compounds with the greatest basophil activity were tested for in vivo activity in the mouse passive cutaneous anaphylaxis (PCA) and the guinea pig passive anaphylaxis tests. The best compounds, 1-ethyl-8-methyl-6-propylimidazo[1,5-d][1,2,4]triazin-4(3H)- one (4-17) and 1,8-dimethyl-6-propylimidazo[1,5-d][1,2,4]triazin-4-(3H)-one (4-16) were chosen for further study.

Anaphylaxis↗

PubMed2004

Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists.

The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, > 400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.

Adenosine A2 Receptor Antagonists↗

PubMed2006

One-pot synthesis of fluorescent 2,5-dihydro-1,2,3-triazine derivatives from a cascade rearrangement sequence in the reactions of 1,2,3-triazolium-1-aminide 1,3-dipoles with propiolate esters.

The reactions of 1,2,3-triazolium-1-aminides 1 (readily available from benzil bishydrazones) with propiolate esters leads to fluorescent 2,5-dihydro-1,2,3-triazine derivatives 2, 3 in one pot. These synthetic reactions can be carried out in acetone, in water, or under solvent-free conditions. The reactions involve a Huisgen cycloaddition followed by a sequence of rearrangements. The final ring-expansion step was blocked by linking a six-methylene hydrocarbon chain between the prospective 1,2,3-triazine C-4 and C-6 atoms, using substrate 8 which gave the fused tricyclic azapropellane product 9 exclusively. X-ray crystal structures were determined for two 2,5-dihydro-1,2,3-triazine derivatives and for compound 9. The UV absorption of the 1,2,3-triazine derivatives showed a dual absorption at ca. 310 and ca. 390 nm with fluorescent emission at ca. 480 and 528 nm (for excitation at 317 nm). The significant Stokes shift of ca. 200 nm shows the potential for biological fluorescent labeling experiments.

Catalysis↗

PubMed1997

Synthesis of glycosides in which the aglycon is an N-(hydroxymethyl)amino-1,3,5-triazine derivative.

The synthesis of analogues of the anti-tumour drug 2-[N-(hydroxymethyl)methylamino]-4,6-bis(dimethylamino)-1,3,5-triazine (HMPMM) in which the OH or a dimethylamino group is replaced by a carbohydrate has been explored. Triazinyl beta-glycosides were readily prepared by reaction of sugars with trimethyl-triazinylammonium salts. These were made with one or two methylamino groups on the triazine for reaction with formaldehyde to give the cytotoxic NMeCH2OH group. However, reaction of the triazinyl glycosides with formaldehyde gave complex intractable mixtures. When the carbohydrate portion was changed to the fully protected 2,3,4,6-tetra-O-acetyl glucose a good yield of the 2-[N-(hydroxymethyl)methylamino]-4-(dimethylamino)-1,3,5-triazin-2 -yl tetra-O-acetyl beta-glucoside was obtained. However, de-acetylation using sodium methoxide also removed the N-CH2OH group. We are investigating protection of the base-sensitive N-CH2OH group as trialkylsilyl and benzyl ethers and are looking at de-acetylation methods that are more selective. We have prepared glycosides in which the sugar is joined through the oxygen of the NMeCH2OH group. Coupling of acetobromoglucose with HMPMM catalysed by silver salts was not successful. Although methyl and cyclohexyl derivatives of HMPMM may be produced in high yields by reaction of HMPMM with methyl and cyclohexyl alcohols under acidic catalysis, production of glycosides in this way gave poor yields. MNDO calculations on reactions of HMPMM helped us devise improved reaction conditions for the condensation of 2,3,4,6-tetra-O-acetyl glucose with HMPMM and its derivatives. The best procedure to generate one of the target glycosides is to react 2,3,4,6-tetra-O-acetyl glucose and formaldehyde with 2-methylamino-4,6-bis(dimethylamino)-1,3,5-triazine. The beta-glycoside product was de-acetylated using potassium carbonate in dry methanol.

Acetylation↗

PubMed2004

Synthesis and analgesic-anti-inflammatory activities of some 1,2,4-triazine derivatives.

A variety of novel N-arylidene-N'-[5-(4-isobutylphenyl)-[1,2,4]-triazin-3-yl] hydrazines 4, carboxylic acid N'-[5-(4-isobutylphenyl)-[1,2,4]-triazin-3-yl] hydrazides 5, triazolotriazines 6 and other related triazine derivatives were synthesized. Several synthetic routes were employed to access the desired compounds from 5-(4-isobutylphenyl)-[1,2,4]-triazin-3-yl hydrazine 3 as a parent compound. The analgesic and anti-inflammatory activities of the synthesized compounds were studied. The results showed that compound 4 g exhibited pronounced analgesic activity, while compound 4f displayed the highest anti-inflammatory activity. Meanwhile, compound 6d evoked dual analgesic-anti-inflammatory effect without any ulcerogenicity.

Animals↗

PubMed2003

Observations on the relationship between triazines and mycobacteria in metal removal fluids.

The purpose of the study was to determine whether hexahydrotriazine ("triazine") bactericides increase the likelihood of elevated mycobacteria growth in metal removal fluids (MRFs). In reaction to an outbreak of hypersensitivity pneumonitis (HP) at a transmission manufacturing facility, machining plants of a large automobile manufacturer were directed to increase the testing of MRF, especially testing for mycobacteria. A working hypothesis was developed that triazine bactericides cause an increase in mycobacteria contamination, which in turn may lead to an increased risk of HP for workers exposed to MRF aerosols. Test results for 277 central MRF systems from nine machining facilities were analyzed for various MRF properties including the presence and type of both bactericide in the MRF formula and bacterial contamination of the MRF. The study included data reflecting usual operating conditions of all of the 277 large MRF systems in the company. The study does not evaluate the effect of tank-side biocide addition. The results show that soluble oils, semi-synthetic, and synthetic MRFs are all capable of supporting mycobacterial growth. The results also demonstrate a highly significant association between routine use of triazine bactericides and mycobacterial contamination of MRF. Based on the hypothesis that mycobacteria are a likely causative agent of hypersensitivity pneumonitis from MRF exposure, it is concluded that elimination of triazines from MRF formulae may be protective against HP in the machining environment.

Anti-Bacterial Agents↗

PubMed2000

2-Chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells: a novel mechanism for estrogenicity?

There is increasing concern that certain chemicals in the environment can cause endocrine disruption in exposed humans and wildlife. Investigations of potential effects on endocrine function have been limited mainly to interactions with hormone receptors. A need exists for the development of alternate in vitro methods to evaluate chemicals for their potential to disturb various endocrine functions via other mechanisms. Our laboratory is using the human H295R adrenocortical carcinoma cell line to examine chemicals for their potential to interfere with the activity and/or expression of several key cytochrome P450 (CYP) enzymes involved in the biosynthesis of steroid hormones. In this report we demonstrated that the commonly used 2-chloro-s-triazine herbicides atrazine, simazine, and propazine dose-dependently (0-30 microM) induced aromatase (CYP19) activity to an apparent maximum of about 2.5-fold in H295R cells. Basal- and triazine-induced aromatase activity was completely inhibited by the irreversible aromatase inhibitor 4-hydroxyandrostenedione (100 microM). The triazines increased levels of CYP19 messenger ribonucleic acid (mRNA) between 1.5- and 2-fold. The time-response profile of the induction of aromatase activity and CYP19 mRNA by the triazines was similar to that by 8-bromo-cyclic adenosine monophosphate, a known stimulant of the protein kinase-A pathway that mediates the induction of aromatase in these cells. The observed induction of aromatase, the rate-limiting enzyme in the conversion of androgens to estrogens, may be an underlying explanation for some of the reported hormonal disrupting and tumor promoting properties of these herbicides in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2005

Triazine herbicides and epithelial ovarian cancer risk in central California.

OBJECTIVE: We sought to determine whether women with ovarian cancer have increased occupational exposure to triazine herbicides. METHODS: A population-based case-control study of incident cases (n=256) and random digit-dialed control subjects (n=1122) was conducted. Participants were administered telephone interviews to obtain agricultural work history. These histories were used with the statewide pesticide usage database to calculate cumulative exposure estimates. The data were analyzed by stratified analysis and unconditional logistic regression techniques. RESULTS: The analysis of ever versus never occupational exposure to triazines demonstrated that cases were slightly but not significantly more likely to be exposed than control subjects (adjusted odds=1.34; 95% confidence interval=0.77-2.33). There was no evidence of a dose-response relationship between triazines and ovarian cancer (P=0.22). CONCLUSIONS: Considered with previous studies and animal laboratory data, the current evidence is not persuasive as to the presence or absence of an association between ovarian cancer and triazine exposure.

Adult↗

PubMed2005

Invertebrate biodiversity in maize following withdrawal of triazine herbicides.

Responses of key invertebrates within Farm Scale Evaluations (FSEs) of maize reflected advantageous effects for weeds under genetically modified herbicide-tolerant (GMHT) management. Triazine herbicides constitute the main weed control in current conventional systems, but will be withdrawn under future EU guidelines. Here, we reappraise FSE data to predict effects of this withdrawal on invertebrate biodiversity under alternative management scenarios. Invertebrate indicators showed remarkably consistent and sensitive responses to weed abundance. Their numbers were consistently reduced by atrazine used prior to seedling emergence, but at reduced levels compared to similar observations for weeds. Large treatment effects were, therefore, maintained for invertebrates when comparing other conventional herbicide treatments with GMHT, despite reduced differences in weed abundance. In particular, benefits of GMHT remained under comparisons with best estimates of future conventional management without triazines. Pitfall trapped Collembola, seed-feeding carabids and a linyphiid spider followed closely trends for weeds and may, therefore, prove useful for modelling wider biodiversity effects of herbicides. Weaker responses to triazines applied later in the season, at times closer to the activity and capture of invertebrates, suggest an absence of substantial direct effects. Contrary responses for some suction-sampled Collembola and the carabid Loricera pilicornis were probably caused by a direct deleterious effect of triazines.

Analysis of Variance↗

PubMed2005

Triazine Inhibits Toxoplasma gondii tachyzoites in vitro and in vivo.

The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine] inhibits Toxoplasma gondii in vitro at nanomolar levels (P < 0.05). The 50% inhibitory concentration (IC(50)) was approximately 50 nM. It is a potent inhibitor in vitro and is also effective in vivo. Administration of WR99210 parenterally (i.e., intraperitoneally) reduced the mean number of RH strain tachyzoites present in peritoneal fluid substantially 4 days after intraperitoneal infection of mice. There was a mean of approximately 35 million parasites in control mice as contrasted with approximately 2 million parasites in mice treated with 1.25 mg WR99210/kg of body weight in a representative experiment (P < 0.05). In addition the prodrug PS-15 N'-[3-(2,4, 5-trichlorophenoxy)propyloxy]-N9-(1-methylethyl) imidocarbonimidicdiamide is converted to 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine in vivo when the prodrug is administered orally. PS-15 administered by gavage also reduced intraperitoneal RH strain T. gondii tachyzoite numbers. WR99210 has high efficacy and relatively low toxicity because of its substantial effect on T. gondii dihydrofolate reductase (DHFR) but not the mammalian host DHFR. Amino acid sequences of T. gondii, Plasmodium falciparum, and Homo sapiens DHFRs were compared. It is of interest that of the DHFR amino acids considered to be interacting with WR99210 in P. falciparum within interatomic distances within 3 to 5 A, four of eight were shared with T. gondii DHFR. H. sapiens also shared four amino acids thought to be interacting with WR99210. Efficacy of intraperitoneal administration of WR99210 and peroral administration of PS-15 demonstrate the potential usefulness of this class of compounds in treatment of toxoplasmosis administered either parenterally or perorally. The recent development program for this class of antimicrobials as antimalarials makes our proof of principle of improved efficacy of triazines (compared with the gold standard treatment, pyrimethamine) against T. gondii especially promising.

Animals↗

PubMed2000

Synthesis and antitumor activity of benzimidazolyl-1,3,5-triazine and benzimidazolylpyrimidine derivatives.

Triamino-substituted 1,3,5-triazine and pyrimidine derivatives were synthesized and tested for antitumor activities using some human cancer cell lines and murine leukemia cell lines. All the compounds having benzimidazolyl and morpholino groups as substituents on the 1,3,5-triazine ring showed antitumor activity. Pyrimidine derivatives having the same groups as substituents also showed antitumor activity. Among them, the compounds having 1-benzimidazolyl, morpholino and cis-2,3-dimethylmorpholino groups as substituents on the 1,3,5-triazine ring or pyrimidine ring exhibited the most potent antitumor activity, and these compounds exhibited no or very weak aromatase inhibitory activity. In contrast, the compounds having imidazolyl group instead of benzimidazolyl group as a substituent on the 1,3,5-triazine ring showed a potent aromatase inhibitory activity.

Animals↗

PubMed1994

Ab initio studies of 2,4-diamino triazine and its complexes with ligands: a model for inhibitor-active site interactions of dihydrofolate reductase.

The protonation energies of 2,4-diamino triazine, an inhibitor of the therapeutic target dihydrofolate reductase, has been calculated using ab initio (Hartree-Fock) calculations. It is found that N1 (see Fig. 1) exhibits the highest proton affinity (261.6 kcal/mol) by comparison with other inhibitor protonation sites. The energies of binding of the formate ion and formamide (as models for the amino acid residues in the active site of dihydrofolate reductase) to neutral and protonated 2,4-diamino triazine are also obtained. The highest binding energies are featured by the complex formed from a formate attached to the N4 and N1 protonated forms of the triazine. However, as N4 has a comparatively low proton affinity (195.0 kcal/mol), it is unlikely that an interaction of this nature would prevail. On the other hand, the formate-protonated N1 interaction is similar to the structures identified by X-ray crystallography of enzyme-triazine complexes.

Binding Sites↗

PubMed1976

Clinical and pharmacological evaluation of triazinate in humans.

Twenty-four patients with advanced solid tumors and seven with acute leukemia were treated with a triazine folate antagonist, triazinate, to determine the toxicity spectrum, the maximum tolerated dose, and the pharmacological disposition of the drug. Negligible toxicity was seen with single doses of 20 to 225 mg/sq m given as a 0.5-hr infusion. Single doses of 300 to 600 mg/sq m infused over 0.5 to 3 hr caused moderate to severe central neurological impairment with light headedness, somnolence, visual disturbances, weakness, and in one patient, severe respiratory distress and cyanosis. Skin, mucous membrane, and bone marrow toxicity were mild to moderate with single doses. When triazinate was given by a multiple-dose schedule every 12 to 24 hr, there was no neurological toxicity, but mucositis, skin toxicity, and myelotoxicity were increased. Five patients developed an erythematous to desquamative rash at the site of previous or concurrent radiotherapy. Serum disappearance of triazinate was at least bionsiderable variation from patient to patient. Single i.v. doses of 300 mg/sq m resulted in serum levels of 10(-5) M or higher for 8 hr and, with repeated doses, this level could be maintained. Administration p.o. resulted in serum concentrations less than 10% of that achieved after i.v. administration. Cerebrospinal fluid concentrations were 2% or less of the serum levels in five or six patients, 1 to 4 hr after i.v. treatment. Urinary excretion varied from 12 to 71% (median, 43%) of the total dose injected during the first 24 hr. Measurable objective solid tumor responses were not seen in this Phase 1 study, although two patients had stabilization of previously advancing disease. Decreases in peripheral blasts occurred in both types of acute leukemia, but improvement in the bone marrow was not observed.

Adolescent↗

PubMed1987

Conformational analysis of lipophilic antifolates: crystal and molecular structures of three s-triazine dihydrofolate reductase inhibitors.

The results of crystal structure determinations on a series of protonated N1-phenyl-substituted 1,2-dihydro-2,2-dimethyl-4,6-diamino-s-triazine anti-cancer antifolates show that the s-triazine ring adopts a twist-sofa conformation with C2 nearly 0.5 A above the plane and the N1-phenyl ring is nearly perpendicular to the s-triazine ring, in agreement with minimum energy calculations and with antifolate binding in the active site of chicken liver dihydrofolate reductase. The 2,2-dimethyl groups are equatorial and axial. Comparison of these s-triazines with analogous pyrimidine antifolates reveals that the axial 2-methyl group occupies the same conformational space as the 6-methyl group in active anti-cancer agents.

Crystallization↗

PubMed1996

Immunological determination of triazine pesticides bound to soil humic acids (bound residues).

An immunological method for the determination of triazine herbicides covalently bound to soil humic acids has been developed. A sandwich-immunoassay has been performed, based on both polyclonal humic acid-antibodies and monoclonal triazineantibodies. A peroxidase-labelled third antibody has been used for the photometric detection. A triazine-humic acid conjugate served as calibration standard. The coupling density for this conjugate has been determined by measuring the difference of free amino groups both with ninhydrin and with the trinitrobenzene sulfonic acid method. In addition, the coupling density has been confirmed by scintillation counting using a (14)C-atrazine derivative. Due to nonspecific interactions between antibody proteins and humic acids, different blocking steps had to be performed. Finally, the assay has been applied to a triazine contaminated soil sample. Humic acids (including bound residues) have been extracted by diluted sodium carbonate solution. Concentrations of bound atrazine residues have been found in the range of 2 mg/kg soil on fields where triazine herbicides has been applied over a period of 21 years. These results are comparable to both the applied amount and the nonextractable fraction.

Journal Article↗

PubMed1998

Soil Adsorption Coefficients of s-Triazines Estimated with a New Gradient HPLC Method.

A high-performance liquid chromatography (HPLC) method employing gradient elution was developed to predict soil adsorption coefficients (K(oc)) from HPLC capacity factors. The gradient method allows for the determination of K(oc) values over a range of 4.4 orders of magnitude in a single experiment without adjustment of the solvent composition, as is required in isocratic HPLC measurements. The range of K(oc) estimated can easily be extended by using reference compounds with lower or higher log K(oc) values. Therefore, gradient HPLC is an appropriate screening method for K(oc) and was used to investigate s-triazine herbicides and their degradation products. Log K(oc) ranged from 0.8 for cyromazine to a maximum of 2.6 for anilazine and aziprotryne. HPLC-derived K(oc) values of s-triazines containing an azido group were higher than and those of hydroxy-s-triazines were lower than K(oc) values estimated according to the fragment contribution method of Meylan et al. (1992). According to this method, the log K(oc) of the keto form of hydroxy-s-triazines was >1 log unit higher than that of the enol form.

Journal Article↗

PubMed2005

Thermal decomposition of energetic materials. 5. reaction processes of 1,3,5-trinitrohexahydro-s-triazine below its melting point.

Through the use of simultaneous thermogravimetry modulated beam mass spectrometry, optical microscopy, hot-stage time-lapsed microscopy, and scanning electron microscopy measurements, the physical and chemical processes that control the thermal decomposition of 1,3,5-trinitrohexahydro-s-triazine (RDX) below its melting point (160-189 degrees C) have been identified. Two gas-phase reactions of RDX are predominant during the early stages of an experiment. One involves the loss of HONO and HNO and leads to the formation of H2O, NO, NO2, and oxy-s-triazine (OST) or s-triazine. The other involves the reaction of NO with RDX to form NO2 and 1-nitroso-3,5-dinitrohexahydro-s-triazine (ONDNTA), which subsequently decomposes to form a set of products of which CH2O and N2O are the most abundant. Products from the gas-phase RDX decomposition reactions, such as ONDNTA, deposit on the surface of the RDX particles and lead to the development of a new set of reaction pathways that occur on the surface of the RDX particles. The initial surface reactions occur on surfaces of those RDX particles in the sample that can accumulate the greatest amount of products from the gas-phase reactions. Initial surface reactions are characterized by the formation of islands of reactivity on the RDX surface and lead to the development of an orange-colored nonvolatile residue (NVR) film on the surface of the RDX particles. The NVR film is most likely formed via the decomposition of ONDNTA on the surface of the RDX particles. The NVR film is a nonstoichiometric and dynamic material, which reacts directly with RDX and ONDNTA, and is composed of remnants from RDX and ONDNTA molecules that have reacted with the NVR. Reactions involving the NVR become dominant during the later stage of the decomposition process. The NVR reacts with RDX to form ONDNTA via abstraction of an oxygen atom from an NO2 group. ONDNTA may undergo rapid loss of N2 and NO2 with the remaining portion of the molecule being incorporated into the dynamic NVR. The dynamic NVR also decomposes and leads to the formation of H2O, CH2O, N2O, NH2CHO, (CH3)2NCHO, (CH3)2NNO, C2H2N2O, and (CH3)3N or CH3NCH2CH3. The competition between reaction of the dynamic NVR with RDX and its own thermal decomposition manifests itself in a rapid increase in the rate of evolution of the NVR decomposition products as the amount of RDX remaining in the sample nears depletion. The reactions between the NVR film and RDX on the surface of the RDX particles leads to a localized environment that creates a layer of molten RDX on the surface of the particles where reactions associated with the liquid-phase decomposition of RDX may occur. The combination of these reaction processes leads to an acceleration of the reaction rate in the later stage of the decomposition process and creates an apparent reaction rate behavior that has been referred to as autocatalytic in many previous studies of RDX decomposition. A reaction scheme summarizing the reaction pathways that contribute to the decomposition of RDX below its melting point is presented.

Journal Article↗

PubMed2006

Non-covalent polymerisation in the solid state: halogen-halogen vs. methyl-methyl interactions in the complexes of 2,4-di(2-pyridyl)-1,3,5-triazine ligands.

Fe(II), Co(II), Ni(II) and Cu(II) complexes based on the triazine ligand 2,4-di(2'-pyridyl)-6-(p-bromo-phenyl)-1,3,5-triazine have been synthesised and characterised. The electrochemical, magnetic and spectroscopic properties of the complexes have also been investigated, and the electron deficient triazine ligand has been shown to affect each of these properties. Further investigation of solid state structures of the ligand and its Fe(II), Co(II) and Cu(II) complexes has established that stabilising Br-Br interactions exist which link neighbouring molecules to form one-dimensional tapes. A slight modification of the ligand, i.e., using 2,4-di(2'-pyridyl)-6-(p-methylphenyl)-1,3,5-triazine, in which the phenyl substituent has changed from a bromine to a methyl group, eliminates the one-dimensional tape and gives rise to significant pi-stacking interactions in the solid state.

Journal Article↗