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PubMed1989

Inhibition of 5-lipoxygenase by substituted 3,4-dihydro-2H-1,4-thiazines.

A series of substituted 3,4-dihydro-2H-1,4-thiazines inhibit 5-lipoxygenase from rat leukocytes and exhibit submicromolar IC50 values. A novel synthesis of these compounds was developed based on the formation of hydroxymethyleneamine 13 and its cyclization to the title compounds. The dihydrothiazines have low oxidation potentials, typically E1/2 is near 0.3 V, and a representative compound reduces Fe(III)(phen)3, with k = 10(5) M-1s-1. We propose that these lipophilic compounds bind to 5-lipoxygenase and reduce the iron in the active site, thus inactivating the enzyme.

Animals↗
PubMed2004

Effect of NO synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine on endotoxin-induced changes in hemodynamic parameters and respiration in rats.

We studied the effect of NO synthase inhibitor 2-amino-5,6-dihydro-4H-1,3-thiazine (2-ADT) on the cardiovascular system in rats with endotoxic shock. Blood pressure, heart rate, and respiratory rate were recorded. E. coli lipopolysaccharide decreased blood pressure and heart rate. 2-ADT in a dose of 5 mg/kg normalized these hemodynamic parameters. The normalizing effect of 2-ADT decreased with increasing the dose of this preparation. 2-ADT in high doses (10, 20, and 30 mg/kg) and repeated injections of the preparation caused death of experimental animals.

Animals↗
PubMed2005

Quaternary ammonium substituted thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides: Potential membrane-impermeable inhibitors of carbonic anhydrase.

Thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides, which have a quaternary ammonium moiety incorporated into their structures, were synthesized. All of the quaternary ammonium salts prepared in the present study are potent inhibitors of both human carbonic anhydrase-II and recombinant human carbonic anhydrase-IV; they are significantly more potent as inhibitors of these carbonic anhydrase isozymes than the previously reported inhibitor quaternary ammonium homosulfanilamide. By virtue of the permanent cationic charge on these compounds they are anticipated to be membrane-impermeable inhibitors of carbonic anhydrase. Spiro quaternary ammonium compounds, such as 15 and 16, when formed by intracellular cyclization following transport of a suitable precursor molecule, such as 14, may be selective prolonged inhibitors of cytosolic carbonic anhydrase due to intracellular entrapment.

Carbonic Anhydrase II↗
PubMed2006

Naphtho[2,3-b][1,4]-thiazine-5,10-diones and 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thioalkanoate derivatives: synthesis and biological evaluation as potential antibacterial and antifungal agents.

A series of 3-substituted-1,4-dioxo-1,4-dihydronaphthalen-2-yl-thio-alkanoate derivatives 3-21 and naphtho[2,3-b][1,4]-thiazine-5,10-diones 24 were synthesized and evaluated for their antibacterial and antifungal activities. The structure-activity relationships of these compounds were studied and the results show that the compound 24a exhibited better antibacterial activity than Gentamycin in vitro against Staphylococcus aureus. In addition 24a also imparted marked antifungal activity in vitro against Cryptococcus neoformans, Sporothrix schenckii, and Trichophyton mentagraphytes when compared with Fluconazole. Compounds 15, 18, 19, and 21 also exhibited significant antibacterial activity in vitro against S. aureus.

Anti-Bacterial Agents↗
PubMed2005

Spectrophotometric investigation of the hetero-association of caffeine and thiazine dye in aqueous solution.

The self-association of thiazine dye, Methylene Blue (MB), and its hetero-association with Caffeine (CAF), were studied in aqueous solution by means of spectrophotometry in the visible range of spectrum. Concentration and temperature dependences of molar absorption of the interacting molecules were used to analyse dynamic equilibrium in solution in terms of two-component model of molecular hetero-association. The magnitudes of equilibrium dimerization and hetero-association constants as well as thermodynamic parameters, enthalpy and entropy, were determined. The calculation of the fraction of different types of associates in the mixed solution, containing Methylene Blue and Caffeine, was done. It was concluded that the hetero-association of Methylene Blue and Caffeine molecules results in lower effective concentration of the dye in solution, which may account for the alteration of its biological activity.

Caffeine↗
PubMed2002

Synthesis of some 1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones with potential analgesic and antiinflammatory activities.

Starting from 3-substituted-1,2,4-triazole-5-thiones (la-h), eight new 5-carbomethoxy-2-substituted-7H-1,2,4-triazolo[3,2-b]-1,3-thiazine-7-ones (2a-h) were synthesized and characterized by spectral and elementary analysis. The obtained compounds were submitted to preliminary pharmacological assay to evaluate their antiinflammatory and analgesic activities as well as gastrointestinal irritation liability and acute toxicity. Among the compounds studied, compounds 2c, 2d, 2e and 2h showed most remarkable antiinflammatory activity in the carrageenan and serotonin induced edema and in the inhibition of castor oil-induced diarrhea tests. The analgesic activity of these active compounds correlated with their antiinflammatory activities in the inhibition of acetic acid-induced writhing test. In gastric ulceration studies, the compounds were found safety at low dose levels (10 and 20 mg/kg).

Acetic Acid↗
PubMedDate not supplied

Liquid-phase parallel synthesis of combinatorial libraries of substituted 6-carbamoyl-3,4-dihydro-2H-benzo[1,4]thiazines.

In this work, we explored several original combinatorial derivatization patterns for the 3,4-dihydro-2H-1,4-benzothiazine scaffold. The synthesis begins with commercially available 4-chloro- and 4-fluoro-3-nitrobenzoates and employs a sequence of moderate and high-yielding reactions that display a relatively high substituent tolerance. Simple manual techniques for parallel reactions were coupled with easy workup and purification procedures to give high-purity final products. The developed approach was easily adaptable for parallel synthesis of more than 2600 novel 2H-benzo[1,4]thiazine-6-carboxylic acid amides, which were efficiently prepared in a semiautomatic fashion using special CombiSyn synthesizers.

Chromatography, Liquid↗
PubMed2002

Development of new fungicides against Magnaporthe grisea: synthesis and biological activity of pyrazolo[3,4-d][1,3]thiazine, pyrazolo[1,5-c][1,3,5]thiadiazine, and pyrazolo[3,4-d]pyrimidine derivatives.

Some pyrazolo[3,4-d]pyrimidin-4(5H)-thione, pyrazolo[3,4-d][1,3]thiazin-4-one/thione, and pyrazolo[1,5-c][1,3,5]thiadiazine-4-one/thione derivatives were synthesized and screened for antifungal activity against the causal agent of rice blast disease, Magnaporthe grisea. In all cases a remarkable inhibition of fungal growth was found in the range from 10 to 200 microg x mL(-1). Several compounds were able to control mycelium growth at a rate of 10 microg x mL(-1), a concentration at which the reference compound tricyclazole was completely ineffective. At least in the case of the most active substance, at the same dose the growth of seedlings or cultured cells of rice was substantially unaffected. Results allowed definition of structural requirements either to maintain or to enhance mycotoxic activity.

Fungicides, Industrial↗
PubMed1983

Synthesis of potential anticancer agents. Pyrido[4,3-b][1,4]oxazines and pyrido[4,3-b][1,4]thiazines.

Hydrolysis of the chloro group of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (3) with formic acid gave the corresponding 4-hydroxypyridine 4. Catalytic hydrogenation of the nitro group of 4 gave the 5-amino-4-hydroxypyridine 5, which was reacted with alpha-halo ketones in acetic acid at room temperature to give a series of 3- and 2,3-substituted ethyl (5-amino-2H-pyrido[4,3-b][1,4]oxazin-7-yl)carbamates 8. Treatment of 8 with hot concentrated hydrochloric acid regenerated the pyridine synthon 5. In the reaction of 3 with thioacetate, the product underwent hydrolysis and air-oxidation to give the corresponding disulfide 6. Simultaneous reduction of both the nitro group and disulfide linkage of 6 gave the 5-amino-4-mercaptopyridine 7, which was reacted with alpha-halo ketones either in acetic acid at room temperature or in a mixture of ethanol and water at reflux to give a series of 3-, 2,3-, and 2,2,3-substituted ethyl (5-amino-2H-pyridol[4,3-b][1,4]thiazin-7-yl)carbamates 9. The effects of these pyridooxazines and pyridothiazines upon the proliferation and the mitotic index of cultured L1210 cells and upon the survival of mice bearing P388 leukemia were determined.

Animals↗
PubMed1996

Expression and immunoaffinity purification of human inducible nitric-oxide synthase. Inhibition studies with 2-amino-5,6-dihydro-4H-1,3-thiazine.

Recombinant human inducible nitric-oxide synthase (rH-iNOS) was expressed in the baculovirus system and purified by a novel immunoaffinity column. rH-iNOS and its native counterpart from cytokine-stimulated primary hepatocytes exhibited similar molecular mass of 130 kDa on SDS-polyacrylamide gel electrophoresis, recognition by antipeptide antibodies, specific activities, and IC50 values for inhibitors. The active dimeric form exhibited a specific activity range of 114-260 nmol/min/mg at 37 degrees C and contained 1.15 +/- 0.04 mol of calmodulin/monomer. The enzyme exhibited a Soret lambdamax at 396 nm with a shoulder at 460 nm and contained 0. 28-0.64 mol of heme/monomer. Dithionite reduction under CO yielded an absorbance maximum at 446 nm, indicating a P450-type heme. Imidazole induced a type II difference spectrum, reversible by L-Arg. 2-Amino-5,6-dihydro-4H-1,3-thiazine (ADT) was competitive versus L-Arg (Ki = 22.6 +/- 1.9 nM), reversed the type II difference spectrum induced by imidazole (Kd = 17.7 nM), and altered the CO-ferrous absorbance of rH-iNOS. L-Arg did not perturb the CO-ferrous adduct directly, but it partially reversed the ADT-induced absorbance shift, indicating that both bind similarly to the protein but interact differently with the heme.

Chromatography, High Pressure Liquid↗
PubMed1989

Actions of the insecticide 2(nitromethylene)tetrahydro-1,3-thiazine on insect and vertebrate nicotinic acetylcholine receptors.

The nitromethylene heterocyclic compound 2(nitromethylene)tetrahydro)1,3-thiazine (NMTHT) inhibits the binding of [125I]alpha-bungarotoxin to membranes prepared from cockroach (Periplaneta americana) nerve cord and fish (Torpedo californica) electric organ. Electrophysiological studies on the cockroach fast coxal depressor motorneuron (Df) reveal a dose-dependent depolarization in response to bath-applied NMTHT. Responses to ionophoretic application of NMTHT onto the cell-body membrane of motorneuron Df are suppressed by bath-applied mecamylamine (1.0 x 10(-4) M) and alpha-bungarotoxin (1.0 x 10(-7) M). These findings, together with the detection of a reversal potential close to that estimated for acetylcholine, provide evidence for an agonist action of this nitromethylene on an insect neuronal nicotinic acetylcholine receptor. The binding of [3H]H12-histrionicotoxin to Torpedo membranes was enhanced in the presence of NMTHT indicating an agonist action at this vertebrate peripheral nicotinic acetylcholine receptor. NMTHT is ineffective in radioligand binding assays for rat brain GABAA receptors, rat brain L-glutamate receptors and insect (Musca domestica) L-glutamate receptors. Partial block of rat brain muscarinic acetylcholine receptors is detected at millimolar concentrations of NMTHT. Thus nitromethylenes appear to exhibit selectivity for acetylcholine receptors and exhibit an agonist action at nicotinic acetylcholine receptors.

Amphibian Venoms↗
PubMed1995

The biological reality of the interlacunar network in the embryonic, cartilaginous, skeleton: a thiazine dye/absolute ethanol/LR White resin protocol for visualizing the network with minimal tissue shrinkage.

Third toe phalanges of chicks aged 8-13 days in ovo and 7-day post-natal rat femoral growth plate were examined to determine whether the interlacunar network (IN), a structure with no lipoprotein membrane component or cytoplasmic organelles, is a genuine component of young growth cartilage. In chick phalanges dehydrated by 70% (v/v) ethanol and LR White resin, variable metachromatic staining of the interlacunar network by toluidine blue and red staining by picro-Sirius red indicate the presence of glycosaminoglycans and collagen. The network in phalanges dehydrated by 80% (v/v) ethanol appears little different; however, the network is much less widely detectable in phalanges dehydrated by 90% (v/v) ethanol and, after dehydration by absolute ethanol, is almost completely undetectable. In contrast, when the young cartilage is permeated by a thiazine dye such as toluidine blue, using a solution of dye in the aldehyde fixative, the network is widely detectable, following dehydration by absolute ethanol, both in chick phalanges and in rat growth plate. Comparison of projected areas shows that the extent to which whole chick feet are found to have shrunk, by the time that they are photographed under LR White resin, is determined principally by the extent of dehydration, by 70% (v/v) or absolute ethanol; post-shrinkage areas are 33% or 35% of areas measured in buffer for 70% (v/v) ethanol/LR White resin and 71% or 75% for absolute ethanol/LR White resin (the higher value in each is for the toluidine blue treatment). The network is thus present in radically shrunk tissue, but, significantly, is also fully represented in tissue shrunk by only a conventional margin and is therefore not produced as an artefact by exceptional tissue shrinkage as has been suggested.

Animals↗
PubMed2003

Effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), an orally active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in models of generalized epileptic seizure in mice and rats.

The anticonvulsant activity of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, was studied in animal models of generalized seizure. YM928 exerted significant anticonvulsant effects in the maximal electroshock (MES) seizure test (ED50 = 7.4 mg/kg p.o.), pentylenetetrazol (PTZ)-induced seizure test (ED50 = 9.6 mg/kg p.o.), AMPA-induced seizure test (ED50 = 5.5 mg/kg p.o.), and strychnine-induced seizure test (ED50 = 14.0 mg/kg p.o.) in mice. Effects in rats were detected in the MES seizure test (ED50 = 4.0 mg/kg p.o.) and PTZ-induced seizure test (ED50 = 6.2 mg/kg p.o.). The profile of YM928 was compared with that of established antiepileptics. Valproate showed beneficial effects in all tests used. In contrast, carbamazepine, phenytoin, lamotrigine, phenobarbital, diazepam, ethosuximide, and gabapentin were not active against seizures induced by at least one stimulant. In the rotarod test, YM928 impaired motor coordination (TD50 = 22.5 mg/kg p.o.). The protective index (TD50 value of the rotarod test/ED50 value of MES seizure) was 3.0, suggesting that YM928 can exert antiepileptic effects with only minor motor disturbances. YM928 at doses of 2, 4, and 8 mg/kg p.o. did not significantly affect the threshold of electroshock seizure in rats after 16 days of repeated administration. These data indicate that YM928 does not induce tolerance after subchronic administration. These results indicate that YM928 is a broad-spectrum anticonvulsant that would prove useful for the treatment of generalized seizure in human epileptic patients.

Animals↗
PubMed1997

Pulmonary endothelial thiazine uptake: separation of cell surface reduction from intracellular reoxidation.

The objective of this study was to further evaluate the hypothesis that the accumulation of thiazine dyes, such as methylene blue, by cultured bovine pulmonary arterial endothelial cells involves reduction on the cell surface, followed by diffusion of the lipophilic reduced form of the dye into the cells and intracellular reoxidation to the relatively membrane-impermeant hydrophilic form. The specific question addressed was whether inhibition of methylene blue uptake by cyanide and azide is via inhibition of extracellular reduction or inhibition of intracellular reoxidation. We used the cell membrane-impermeant ferricyanide ion as a secondary electron acceptor to measure the extracellular reduction of methylene blue independently from its uptake by the cells. In addition, toluidine blue O, incorporated into an acrylamide polymer so that it could not permeate the cells in either its reduced or oxidized forms, was used to examine the effects of cyanide and azide on the extracellular reduction. Microscopic observations of the effect of the inhibitors on the intracellular accumulation of methylene blue were also made. The results indicate that the reduction and intracellular sequestration are separate processes and that, in doses that inhibited intracellular reoxidation, and therefore uptake and sequestration, neither cyanide nor azide had an inhibitory effect on extracellular reduction. The intracellular distribution of the observable oxidized form of the dye was consistent with oxidation of the reduced dye within subcellular organelles. The demonstration that extracellular reduction and intracellular sequestration are separate events is consistent with the hypothesized sequence of events.

Acrylic Resins↗
PubMed1988

Cardiotonic activity of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one hydrochloride (ZSY-27).

Cardiotonic activity of a new, non-catecholamine and non-glycoside positive inotropic agent, 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one hydrochloride (ZSY-27), was investigated in isolated guinea pig left atria, cat right ventricular papillary muscle and cross-circulated excised dog papillary muscle preparations, and in anesthetized open-chest dogs. In electrically driven guinea pig left atria and cat papillary muscle preparations, ZSY-27 (3 x 10(-6)-10(-4) M) increased the developed tension in a concentration-related manner. The positive inotropic effect of ZSY-27 was not blocked by propranolol (3 x 10(-8) M) in the guinea pig atria, but was significantly inhibited by carbachol (5 x 10(-6) M) in cat papillary muscle preparations. The positive inotropic effect of ZSY-27 was comparable to that of milrinone in guinea pig atria. ZSY-27 (0.01-3 mg) increased dose-dependently the developed tension in cross-circulated excised dog papillary muscle preparations as well. In anesthetized dogs, ZSY-27 (0.03-1 mg/kg, i.v.) produced a dose-dependent increase in left ventricular contractile force and a decrease in blood pressure, while the increase in heart rate was relatively small. The pharmacological profile of ZSY-27 in anesthetized dogs was similar to that of milrinone. These results suggest that ZSY-27 is potent cardiotonic agent with vasodilator activity and its effect may be partially due to an increase in the intracellular adenosine 3',5'-cyclic monophosphate level.

Animals↗
PubMed1989

Effects of a new positive inotropic agent with a vasodilatory action, 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), on agonists-induced contractions in the isolated rabbit thoracic aorta.

The mechanism of the vasodilatory effect of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a non-catecholamine and non-glycoside positive inotropic agent with a vasodilatory action, was investigated using helically-cut strips of the rabbit thoracic aorta. The contractile responses of the thoracic aorta to phenylephrine and prostaglandin F2 alpha were antagonized noncompetitively in a concentration-dependent manner by ZSY-27 (1 x 10(-4) - 1 x 10(-3) M). Furthermore, precontractions induced by high K (34.5 mM K) and by phenylephrine (1 x 10(-6) M) were relaxed in a concentration-dependent manner by ZSY-27 (1 x 10(-6) - 1 x 10(-3) M). These relaxant effects were not affected by a decrease in extracellular Ca or by pretreatment with methylene blue, an inhibitor of guanylate cyclase, but were significantly potentiated by pretreatment with forskolin, a direct stimulator of adenylate cyclase. Moreover, the amount of Ca stored in smooth muscle cells was estimated from the amplitude of the phasic contractions induced by phenylephrine in Ca-deprived medium. The first phasic contraction induced by phenylephrine was inhibited by pretreatment with ZSY-27. After ZSY-27 was washed out with a Ca-deprived solution, the second phasic contraction induced by phenylephrine occurred manifestly, but not in preparations untreated with ZSY-27. It is concluded that ZSY-27 caused a nonspecific relaxation of arterial smooth muscle contractility mainly by acting on some processes distal to adenosine 3',5'-monophosphate (cAMP) production by adenylate cyclase; probably inhibition of cAMP-phosphodiesterases.

Animals↗
PubMed1989

Relationship between cyclic nucleotide levels and 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a new positive inotropic agent with a vasodilatory action, -induced relaxation of rabbit thoracic aorta.

The aim of this investigation was to substantiate the hypothesis that the vasorelaxant effects of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27) are mediated by accumulation of intracellular cyclic nucleotides as a consequence of inhibition of cyclic nucleotide phosphodiesterase activity. Both activities of adenosine 3',5'-monophosphate-phosphodiesterase (cAMP-PDE) in the presence of ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) and guanosine 3',5'-monophosphate-phosphodiesterase (cGMP-PDE) in the presence of calcium-calmodulin from rabbit thoracic aorta were inhibited in a concentration-dependent manner by ZSY-27 (10(-5) - 10(-3) M). The IC50 values for ZSY-27 on cAMP- and cGMP-PDE activity were 2.1 x 10(-4) and 8.8 x 10(-4) M, respectively. Furthermore, ZSY-27 antagonized competitively cAMP-PDE (Ki = 1.9 x 10(-4) M). On the other hand, ZSY-27 exhibited a mixed-type inhibitory pattern, with reduction of both maximum velocity and affinity for the substrate of the cGMP-PDE, with a Ki value of 1.0 x 10(-3) M. Spontaneous myogenic tone of rabbit thoracic aorta was significantly attenuated from 1 min after addition of ZSY-27 (3 x 10(-4) M). Contents of cAMP and cGMP were significantly increased from 1 and 3 min after addition of ZSY-27, respectively. Temporally, relaxant effects of ZSY-27 were associated with increases of cAMP content, but not with that of cGMP content.(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1989

Effects of a new positive inotropic agent with a vasodilatory action, 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), on calcium-movement and mechanical response in rabbit thoracic aorta.

The effects of 5-methyl-6-(4-pyridyl)-2H-1,4-thiazin-3(4H)-one (ZSY-27), a positive inotropic agent with a vasodilatory action, on a concentration-response curve of CaCl2 in the KCl-depolarized rabbit thoracic aorta and Ca-uptake by the microsomal fraction from the rabbit artery were tested. ZSY-27 (10(-5) - 10(-4) M) inhibited noncompetitively a concentration-response curve of CaCl2 in the KCl-depolarized preparation. Furthermore, ZSY-27 (10(-5) M) stimulated significantly Ca-uptake by the microsomal fraction in the presence of oxalate, as an indicator for Ca-uptake by the internal membrane, in every incubation time. However, it inhibited significantly that in the absence of oxalate, as an indicator for Ca-uptake by the plasma membrane-derived vesicle, after 6 min of incubation time. These results suggest that ZSY-27 stimulates Ca-uptake by the internal membranes and inhibits Ca-uptake by the plasma membrane-derived vesicles. Therefore, these effects of ZSY-27 are considered to be related to relaxation of vascular smooth muscle.

Animals↗