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Cyclocondensation of 1-aryl-2-hydrazinoimidazolines with pyruvic acid furnished novel derivatives of imidazo [2,1-c] [1,2,4]triazin-4-one.
The potential risk to wildlife from exposure to explosives, including 1,3,5-trinitro-1,3,5-triazine (RDX), has been an issue at numerous U.S. military installations where these substances are found in soil and water. Presently, no data describing the effects of RDX exposure in avian species exist. Therefore, an acute lethal dose (ALD) and 14- and 90-d subchronic dietary exposures to RDX were evaluated in a species potentially present at many contaminated sites, i.e., the northern bobwhite (Colinus virginianus). The ALDs for females and males were 187 and 280 mg/kg, respectively. Data from the 14-d dietary trial suggested that RDX exposure inhibited food consumption, weight gain, and egg production. Dietary RDX exposure for 90-d produced a dose-dependant decreasing trend in total feed consumption, total egg production, and hen-housed production parameters. These collective data suggest that quail may respond differently to oral RDX exposure compared with mammals.
A Triazin-derivative from a group of industrial chemicals was found to cause cataracts in albino rats during a subchronic toxicity study. To get more insight into this effect, a study was designed with 20 albino (Wistar) and 40 pigmented (black-hooded FB 30) rats using different dosages of the test compound. In a 3 months study period, all rats were photographed with a Scheimpflug camera TOPCON SL-45 3 times, at a baseline examination, prior to any treatment, in the middle and at the end of the study period, prior to sacrifice. The black-and-white film (Kodak T-Max 400R) was standardly developed and evaluated with a Joyce-Loebl microdensitometer in 3 regions of the lens, the capsule, the cortex and the nucleus. The density data from the second and third examination clearly demonstrate that cataract development in the albino rats takes place in the cortical region, whereas in the pigmented rats it takes place in the cortical and partly in the nuclear region. In addition, one albino and two pigmented animals of the groups investigated developed bilateral mature cataracts. Differences in cataract morphology between albino and pigmented rats are presented by Eiben and Wegener (1). The results underline the importance of toxicity testings in pigmented rats, they evidence that the data derived solely from albino animals can be misleading.
Copper complexes of hydrazones derived from symmetrical triazines inhibit the multiplication of three different types of viruses (Sendai, HSV and VSV) showing as well a scavenger activity on O2- radicals. The results emphasize the antiviral activity of these complexes which have at the same time a O2- radical scavenger activity.
A new series of 5-substituted 3-methylisoxazole[5,4-d] 1,2,3-triazin-4-one derivatives was prepared and investigated. The immunological activities of the studied compounds were investigated in two murine models of the immune response to sheep erythrocytes (SRBC)--the humoral immune response and delayed type hypersensitivity (DTH). Quantum-chemical calculations were carried out using AM1, a semiempirical method for geometry optimization, estimation of descriptors values and localization of the HOMO and LUMO orbitals.
Trisethylene-imino-s-triazine (triethylene melamine or TEM) produced minimal effects in inhibiting transplantable lymphoma and mammary adenocarcinoma in mice. In strain A mice, injection of the compound induced pulmonary tumors.TEM was tried on 32 patients with neoplastic disease, including nine patients with Hodgkin's disease and five with lymphosarcoma and lymphatic leukemia. The therapeutic and toxic effects were similar to those observed with nitrogen mustard (HN2). Satisfactory remissions of up to three months were observed in Hodgkin's disease and lymphosarcoma following parenteral administration of TEM. It is the authors' impression that the remissions obtained with TEM were not as complete and did not last as long as those obtained with HN2.TEM is effective by the oral route as well as parenterally, and produces much less emetic reaction than HN2. On the other hand, the chemotherapeutic range is narrower than that of HN2. Patients who do not respond to HN2 show no response to TEM.TEM is a drug of some clinical usefulness in the same conditions and with the same general limitations and toxic effects as HN2. The ease of administration of TEM increases its hazards, and close clinical and hematologic observations are essential on patients receiving the agent.
Reaction of 7-hydroxy-4-methyl coumarin with amido/ imido alcohols in ethanol containing concentrated hydrochloric acid afforded 8-aralkyl amido/imido-alkyl-7-hydroxy-4-methyl-coumarins (1a-f). Interaction of 1a-f with hydrazine hydrate in pyridine resulted in 1-amino-8-aralkyl amido/imido-alkyl-7-hydroxy-4-methyl-2-oxo-quinolines (2a-f). Treatment of 2 with formaldehyde in ethanol resulted in 1,3,5-tris-(8-aralkyl amido/imido-alkyl-7-hydroxy-4-methyl-2-oxo-quinolinyl)-2,4,6-hexahydro-s-triazines (3a-c). Antiviral activity of compounds 2a-d and 3a, 3b upon Japanese encephalitis virus (JEV) and Herpes simplex virus-1 (HSV-1) was evaluated on vero cells in vitro. 3a-c were also screened for their antihypertensive activity.
Cyclocondensation of 1-aryl-2-hydrazono-imidazolidínes with ethyl phenylglyoxylate furnished a novel derivatives of imidazo[2,1-c][1,2,4]triazine.
A new synthetic protocol which considerably improves the classic REMA procedure is proposed herein. The offered modification is based on the application of triazine "superactive esters" as the superior substitutes for mixed anhydrides, which have been used as acylating reagent in the classic procedure. The improved repetitive procedure in solution was applied to the preparation of [54-59] fragment of human beta-casein. The structure and high purity of the intermediates, as well as of the final products, was confirmed by FAB-MS, 1H-NMR and HPLC.
The synthesized fused 1,2,4-triazines were tested for their potential antimicrobial activity resulting from the literature data. Microbiological screening tests conducted in relation to 54 strains of Gram-positive and 52 strains of Gram-negative bacteria, 6 strains of yeast-like fungi and 3 strains of moulds showed that these compounds in examined concentrations 100 mg ml(-1) and 200 mg ml(-1) had no influence on the growth of microorganisms tested. The microbiological screening tests afforded to limit the possible biological spectrum of activity of tested compounds.
N-terminal fragment of emerimicin III has been synthesized by the repetitive method in solution, involving triazine ,,superactive esters". The synthetic protocol, equivalent to the classic REMA procedure, has been applied in the step by step approach, and in the fragment coupling affording all the peptide bonds. By monitoring the progress of the synthesis by FAB-MS, 1H-NMR and HPLC, the structure and high purity of the final products have been confirmed.
Some new fluorine containing substituted 3-thioxo-1,2,4-triazin-5-ones (2-17) have been synthesized and evaluated for in vitro anti human immune virus (HIV) activity. Most of the new compounds displayed a lethal activity, while compounds 2, 6, 7, 10, 11 and 14 displayed a significant antiviral activity. The structures are supported by elemental analysis, IR, UV and 1H-NMR spectral data.
A series of 4,6,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo [3,4-d]pyrimidin-7-ones (1b-n) and 1,4,6,7,8,9-hexahydropyrazolo [3',4':4,5]pyrimido [2,1-c][1,2,4]triazin-7-ones (2a-d) has been synthesized. In view of their potential anti-aggregating activity the compounds were tested in vitro for inhibitory activity towards ADP- and collagen-induced aggregation of human platelets. Among the compounds studied, 8-benzyl-1-(2,5-dichlorophenyl)-4,6,7,8-tetrahydro-1H-imidazo [1,2-a]pyrazolo[3,4-d]pyrimidin-7-one (1n) exhibited the most favorable activity. The 2,5-dichlorophenyl side chain is an important lipophilic and/or steric pharmacophore.
Trimelamol is a synthetic s-triazine carbinolamine-containing agent exhibiting poor aqueous solubility and stability characteristics. The present studies were conducted to provide a stable parenteral dosage form of trimelamol, which could be used for clinical evaluation of the drug and also be manufactured on a commercial scale without undue drug decomposition occurring. Solubility and stability of trimelamol were found to increase in the presence of aqueous-polyethylene glycol (PEG) solutions of increasing average PEG molecular weight (up to mol wt = 1000); PEG 1000 (75%) in water provided the optimum formulation vehicle. In contrast to the optimum liquid formulation of the drug (detailed above) it was necessary to make various compromises to the formulation in terms of drug solubility and stability, because of the problems encountered in processing (e.g., sterile filtration, lyophilization, and reconstitution). Freeze-drying of the formulation extended the product shelf-life relative to the liquid formulation. Differential Scanning Colorimetry (DSC) studies, to determine the freeze-drying cycle parameters, showed that the freezing and melting characteristics of the trimelamol-PEG formulations were dependent upon the rate of cooling, as well as the concentration and average molecular weight of PEG used. The prototype containing 30 mg/mL trimelamol in a 50% PEG 3400-aqueous vehicle was found to be the optimal formulation for sterile filtration, lyophilization, and subsequent reconstitution. Through the use of in vitro techniques, the possibility of hemolysis occurring upon injection resulting from the inclusion of high molecular weight PEGs in the vehicle, was shown to be unlikely.
The interaction of glucose-6-phosphate dehydrogenase (EC 1.1.1.49) from Pseudomonas W6 with 33 triazine dyes bound to poly(ethylene glycol) has been screened by means of affinity partition in an aqueous two-phase system composed of poly-(ethylene glycol) and dextran. Regarding the strength of interaction expressed by the affinity partitioning effect three groups of dyes can be distinguished showing high, medium or low interaction to the enzyme. The different influence of the structurally related dyes Cibacronblue F3G-A, Procion Blue MX-3G and Procion Blue MX-R on the partitioning of glucose-6-phosphate dehydrogenase is discussed. Both coenzymes of this glucose-6-phosphate dehydrogenase, NADP+ and NAD+, are able to diminish the dye-enzyme interactions but to a different extent. In the case of Procion Red HE-3B less than 0.2 mM of NADP+ abolished completely the dye-protein interaction indicating that the dye binding site might be closely related to the nucleotide binding site. This does not hold for a series of other dyes revealing strong interactions to the enzyme. In these cases higher NADP(+)-concentrations are necessary to weaken the dye-enzyme interactions. Only small influences on the interaction between the dye and glucose-6-phosphate dehydrogenase were found with 1 mM NAD+. The different effects of the two coenzymes are discussed with respect to separate binding sites for them and to different conformational states induced. The competition of Procion Red HE-3B with NADP+ and NAD+ for the binding site of glucose-6-phosphate dehydrogenase was also demonstrated by inhibition studies. The Ki-values of Procion Red HE-3B with NAD+ and NADP+, respectively, were calculated.
After structure-activity relationship studies (SAR) on a novel class of substituted thiazolo(3,2-b)(1,2,4)triazin-7-ones, HWA-131 (3-(3,5-di-tert.butyl-4-hydroxyphenyl)-7H-thiazolo(3,2-b)(1,2,4)triaz in-7-one) was selected for incremental pharmacological investigations. This compound was effective in not only preventing, but also curing established arthritic disorders of rats such as adjuvant and type II collagen arthritis as well as those of mice such as chronic graft-versus-host (CGVH) disease, a model for systemic lupus erythematosus (SLE). Further, this non-immunosuppressive drug effectively inhibited the carrageenan-induced paw oedema, attenuated the active Arthus reaction, and demonstrated antierythema as well as antipyretic activity. Part of the antiinflammatory effects of this new compound is most probably related to its antioxidative activity, as well as inhibition of lipoxygenase metabolites. HWA-131's good gastric tolerance may have to do with its limited ability to inhibit the production of cyclooxygenase metabolites. Based on our data, we are sure that HWA-131 will be an effective nonsteroidal antiinflammatory agent, with immunomodulating properties, to combat human autoimmune disorders.
QSAR studies have been performed on the homologues of 3-triazines, using molecular connectivity index and van der Waal volume as structural parameters. The regression analysis has shown good correlation between antitumour activity and the two structural parameters.
The O2- scavenging activity of some ligands of asymmetrical triazine seems to be enhanced when complexed with copper. S1 Cu complex in concentration of 10(-8) M inhibits the multiplication of type 1 (Sendai) parainfluenza virus cultivated on MCA fragments. The possible mechanism of inhibition is discussed.