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PubMed2005

Joint toxicity of triazine herbicides and organophosphate insecticides to the midge Chironomus tentans.

A series of recent studies demonstrated that the triazine herbicide atrazine, although not itself acutely toxic, potentiated the toxicity of certain organophosphate insecticides (OPs) to the midge Chironomus tentans. In the current study, a series of triazine herbicides and triazine herbicide degradation products were tested to determine if other triazines potentiate OP toxicity to midges. Chlorpyrifos and diazinon were the OPs tested. Toxicity tests were conducted using a factorial design and analysis of variance to statistically determine if each triazine had an effect on expected toxicity. Log-probit procedures were also used to evaluate the magnitude of change in median effective concentration (EC50) values during coexposure with each triazine. All of the triazine herbicides tested (atrazine, simazine, cyanazine, and hexazinone) were capable of potentiating the toxicity of the OPs, whereas the degradation products (s-triazine, deethylatrazine, and deisopropylatrazine) had less effect. In most cases, a triazine concentration of 100 microg/L was necessary to significantly increase OP toxicity, and higher concentrations of triazine caused a greater degree of potentiation. Changes in EC50 values ranged from no change to a 2.5-fold increase in toxicity. Generally, EC50 values changed by less than a factor of 2, indicating that the effect may be of limited concern in regard to future risk assessments of OPs.

Animals↗

PubMed2005

Pre-treatment effects of trichloroethylene on the dermal absorption of the biocide, triazine.

Triazine is often added to cutting-fluid formulations in the metal-machining industry as a preservative. Trichloroethylene (TCE) is a solvent used for cleaning the cutting fluid or oil from the metal product. The purpose of this study was to examine the effect of TCE on the dermal absorption of triazine in an in vitro flow-through diffusion cell system. Skin sections were dosed topically with aqueous mixtures containing mineral oil or polyethylene glycol (PEG) spiked with (14)C-triazine. Some skin sections were simultaneously exposed to TCE while other skin sections were pre-treated with TCE daily for 4 days in vivo and then exposed to these mixtures in vitro. TCE pre-treatment almost doubled triazine permeability, but this pre-treatment had no effect on triazine diffusivity. The pre-treatment effects of TCE on triazine permeability appear to be more important in PEG-based mixtures than in the mineral oil-based mixtures. Simultaneous single exposure to TCE had little or no effect on triazine absorption. TCE absorption was significantly less than triazine absorption; however, cutting fluid additives had a more significant effect on TCE absorption than on triazine absorption. In summary, this study demonstrated that TCE pre-treatment can significantly alter the dermal permeability to triazine, and workers who are chronically exposed to this or similar cleansers may be at increased risk of absorbing related skin irritants.

Animals↗

PubMed1994

Purification and Characterization of an Inducible s-Triazine Hydrolase from Rhodococcus corallinus NRRL B-15444R.

The widespread use and relative persistence of s-triazine compounds such as atrazine and simazine have led to increasing concern about environmental contamination by these compounds. Few microbial isolates capable of transforming substituted s-triazines have been identified. Rhodococcus corallinus NRRL B-15444 has previously been shown to possess a hydrolase activity that is responsible for the dechlorination of the triazine compounds deethylsimazine (6-chloro-N-ethyl-1,3,5-triazine-2,4-diamine) (CEAT) and deethylatrazine (6-chloro-N-isopropyl-1,3,5-triazine-2,4-diamine) (CIAT). The enzyme responsible for this activity was purified and shown to be composed of four identical subunits of 54,000 Da. Kinetic experiments revealed that the purified enzyme is also capable of deaminating the structurally related s-triazine compounds melamine (2,4,6-triamino-1,3,5-triazine) (AAAT) and CAAT (2-chloro-4,6-diamino-1,3,5-triazine), as well as the pyrimidine compounds 2,4,6-triaminopyrimidine (AAAP) and 4-chloro-2,6-diaminopyrimidine (CAAP). The triazine herbicides atrazine and simazine inhibit the hydrolytic activities of the enzyme but are not substrates. Induction experiments demonstrate that triazine hydrolytic activity is inducible and that this activity rises approximately 20-fold during induction.

Journal Article↗

PubMed2006

Reactions of hydrated electrons with triazine derivatives in aqueous medium.

A study is made of the kinetics and mechanism of the reaction of radiolytically produced hydrated electron (e-(aq)) with some triazine derivatives [1,3,5-triazine (T), 2,4,6-trimethoxy-1,3,5-triazine (TMT), 2,4-dioxohexahydro-1,3,5-triazine (DHT), 6-chloro N-ethyl N-(1-methylethyl)-1,3,5-triazine 2,4-diamine (atrazine, AT), and cyanuric acid (CA)] in aqueous medium using pulse and steady-state radiolysis techniques. The second-order rate constants were determined from the pseudo first-order decay of e(-)(aq) in the presence of triazines at 720 nm, and the values obtained with T, TMT, AT, and CA are in the order of 10(9) dm(3) mol(-1) s(-1) and that of DHT was 10(8) dm(3) mol(-1) s(-1) at pH 6. The transient absorption spectra from the reaction of e(-)(aq) with T and TMT are characterized by their lambda(max) at 310 nm, and those of DHT and CA are around 280 and 290 nm, respectively. However, a very weak and featureless absorption spectrum is obtained from AT. On the basis of the spectral evidence and on the quantitative electron transfer from the transient intermediates to the oxidant, methyl viologen (MV(2+)), the intermediate radicals are assigned to N-protonated electron adducts (with the unpaired spin density at carbon) of triazines. The degradation profiles, monitored as the disappearance of parent triazine concentrations as a function of dose, obtained with AT, TMT, CA, and DHT, highlight the potential use of e-(aq) in the degradation of triazines.

Electrons↗

PubMed2004

Sorption-desorption behavior of triazine and phenylurea herbicides in Kishon river sediments.

Sorption and desorption hysteresis of widely applied triazine and phenylurea herbicides were studied for river sediments. Organic carbon normalized sorption coefficient (K(OC)) values for all herbicides were significantly higher for the sediment from the downstream region of the river vs. the upstream sediment. On the basis of the measured K(OC) values, the triazine herbicides can be arranged in the following order: terbutryn > terbuthylazine > ametryn > atrazine. Among the phenylurea herbicides, chlorotoluron exhibited higher sorption than isoproturon (K(OC) values of 137 vs. 60 and 228 vs. 125 L/kg for the upstream and downstream sediments, respectively). Moreover, chlorotoluron exhibited lower desorption potential as compared with isoproturon (apparent hysteresis index values were 0.2-0.3 for chlorotoluron vs. 0.6-0.9 for isoproturon, measured with the upstream sediment). High sorption affinity of chlorotoluron to the sediments is probably due to stronger H-bonding interactions of the herbicide molecules with the sorbents. For both phenylurea herbicides, desorption hysteresis increased with decrease in sorbed amount. This behavior was opposite to the hysteresis trend observed for the triazines. The Cl-triazines (atrazine and terbuthylazine) exhibited higher desorption hysteresis than the S-triazines (ametryn and terbutryn). Therefore, the apparent hysteresis index values calculated for the Cl-triazines were lower than the values of S-triazines (about 0.4 and 0.7, respectively). Based on the relative strength of H-bonding interactions of Cl- and S-triazines with formate anion and on the desorption hysteresis data we suggest a gradient-derived hole-filling sorption mechanism for the triazine herbicides with the river sediments.

Adsorption↗

PubMed1999

Mode of action of novel 2-(benzylamino)-4-methyl-6-(trifluoro- methyl)-1,3,5-triazine herbicides: inhibition of photosynthetic electron transport and binding studies.

Novel 2-(benzylamino)-4-methyl-6-(trifluoromethyl)-1,3,5-triazines have the same 1,3,5-triazine skeleton as atrazine, although some of them, for example, 2-(3-chlorobenzylamino)-4-methyl-6-(trifluoromethyl)-1,3,5-tria zin e [pI(50)(spinach) = 7.21], show a >3 times stronger photosynthetic electron transport inhibitory activity than atrazine [pI(50)(spinach) = 6.72]. The new triazines have only one amino group at the triazine ring, and their molecular shapes are different from atrazine. The replacement of the bound [(14)C]atrazine by 1,3,5-triazines was tested to determine whether the novel 1,3,5-triazine analogues exhibit the same binding pattern at the D1-protein as atrazine. It was found that [(14)C]atrazine bound to the D1-protein was replaced by the triazine tested by a clearly competitive interaction. Obviously, the novel 1,3,5-triazines are attached to the same binding niche as atrazine.

Electron Transport↗

PubMed1996

Mortality among workers at two triazine herbicide manufacturing plants.

Triazine herbicides, used extensively in the United States, have not been assessed adequately for carcinogenicity in humans. This study evaluated the mortality experience during the period 1960-1986 of 2,683 men with definite or probable manufacturing exposure to triazine herbicides and 2,234 men with possible exposure to triazines. Standardized mortality ratios (SMRs) were computed as the observed numbers of deaths among study subjects divided by the numbers expected on the basis of general population mortality rates. Subjects with definite or probable exposure to triazines had a favorable mortality experience, compared with U.S. men [all causes, SMR = 72, 95% confidence interval (CI) = 58-89; all cancer, SMR = 85, CI = 46-142]. This group had an increase in deaths from non-Hodgkin's lymphoma (NHL) (3 observed/0.78 expected, SMR = 385, CI = 79-1,124). Two of the decedents with NHL had worked for less than 1 year in triazine-related jobs. Among the 2,234 subjects with possible triazine-related work, the mortality rate for all causes combined was similar to the rates of U.S. men. There was only one confirmed death from NHL. On balance, the results were consistent with previous investigations, which have found no convincing evidence of a causal link between triazines and cancer. However, the exposed cohorts were relatively young and had, on average, only 18 years of follow-up. In particular, results were imprecise for subjects having both a long duration of exposure and long potential induction periods.

Adult↗

PubMed2002

Computational chemistry study of the environmentally important acid-catalyzed hydrolysis of atrazine and related 2-chloro-s-triazines.

Many chlorine-containing pesticides, for example 2-chloro-s-triazines, are of great concern both environmentally and toxicologically. As a result, ascertaining or predicting the fate and transport of these compounds in soils and water is of current interest. Transformation pathways for 2-chloro-s-triazines in the environment include dealkylation, dechlorination (hydrolysis), and ring cleavage. This study explored the feasibility of using computational chemistry, specifically the hybrid density functional theory method, B3LYP, to predict hydrolysis trends of atrazine (2-chloro-N4-ethyl-N6-isopropyl-1,3,5-triazine-2,4-diamine) and related 2-chloro-s-triazines to the corresponding 2-hydroxy-s-triazines. Gas-phase energetics are described on the basis of calculations performed at the B3LYP/6-311++G(d,p)//B3LYP/6-31G* level of theory. Calculated free energies of hydrolysis (delta h G298) are nearly the same for simazine (2-chloro-N4,N6-diethyl-1,3,5-triazine-2,4-diamine), atrazine, and propazine (2-chloro-N4,N6-di-isopropyl-1,3,5-triazine-2,4-diamine), suggesting that hydrolysis is not significantly affected by the side-chain amine-nitrogen alkyl substituents. High-energy barriers also suggest that the reactions are not likely to be observed in the gas phase. Aqueous solvation effects were examined by means of self-consistent reaction field methods (SCRF). Molecular structures were optimized at the B3LYP/6-31G* level using the Onsager model, and solvation energies were calculated at the B3LYP/6-311++G(d,p) level using the isodensity surface polarizable continuum model (IPCM). Although the extent of solvent stabilization was greater for cationic species than neutral ones, the full extent of solvation is underestimated, especially for the transition state structures. As a consequence, the calculated hydrolysis barrier for protonated atrazine is exaggerated compared with the experimentally determined one. Overall, the hydrolysis reactions follow a concerted nucleophilic aromatic substitution (SNAr) pathway.

Acids↗

PubMedDate not supplied

Determination of susceptibility of S-triazine herbicides to protonation and hydrolysis by mineral surfaces.

The relative ease of protonation and/or hydrolysis of s-triazine herbicides due to reactions on soil mineral surfaces may be measured by exposure of films of calcium-saturated montmorillonite to chloroform solutions of the s-triazines for appropriate time periods. s-Triazines susceptible to protonation are transformed into organic cations and adsorbed into the interlamellar region of the montmorillonite. Upon interlamellar adsorption of the s-triazine the concentration becomes sufficiently high to be detected by infrared techniques in the 1500 to 1800 cm-1 region. Hydrolysis of the triazines due to the "surface acidity" of the mineral surface is indicated by formation of a carbonyl band having a frequency at about 1750 cm-1. The relative degree of protonation and hydrolysis has been measured for twenty-seven chloro-, bromo-, methoxy-, and methylthio-s-triazines. These observations aid in predicting physiochemical behavior of s-triazines in soils as well as formulations containing similar mineral surfaces.

Bentonite↗

PubMed2001

Predicting the joint algal toxicity of multi-component s-triazine mixtures at low-effect concentrations of individual toxicants.

Herbicidal s-triazines are widespread contaminants of surface waters. They are highly toxic to algae and other primary producers in aquatic systems. This results from their specific interference with photosynthetic electron transport. Risk assessment for aquatic biota has to consider situations of simultaneous exposure to various of these toxicants. In tests with freshwater algae we predicted and determined the toxicity of multiple mixtures of 18 different s-triazines. The toxicity parameter was the inhibition of reproduction of Scenedesmus vacuolatus. Concentration-response analyses were performed for single toxicants and for mixtures containing all 18 s-triazines in two different concentration ratios. Experiments were designed to allow a valid statistical description of the entire concentration-response relationships, including the low concentration range down to EC1. Observed effects and effect concentrations of mixtures were compared to predictions of mixture toxicity. Predictions were calculated from the concentration-response functions of individual s-triazines by applying the concepts of concentration addition and independent action (response addition) alternatively. Predictions based on independent action tend to underestimate the overall toxicity of s-triazine mixtures. In contrast, the concept of concentration addition provides highly accurate predictions of s-triazine mixture toxicity, irrespective of the effect level under consideration and the concentration ratio of the mixture components. This also holds true when the mixture components are present in concentrations below their individual NOEC values. Concentrations statistically estimated to elicit non-significant effects of only 1% still contribute to the overall toxicity. When present in a multi-component mixture they can co-operate to give a severe joint effect. Applicability of the findings obtained with s-triazines to mixtures of other contaminants in aquatic systems and consequences for risk assessment procedures are discussed.

Chlorophyta↗

PubMed1987

Quantitative structure-activity relationship of triazine-antifolate inhibition of Leishmania dihydrofolate reductase and cell growth.

Quantitative structure-activity relationships have been formulated for the inhibition of Leishmania major dihydrofolate reductase (DHFR) and for inhibition of promastigote cell growth by a series of 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(3-substituted-phenyl)-s-triazine s. The inhibition of DHFR is best correlated by a modified variable for hydrophobicity of the 3-X substituent (pi'3), an alkoxy group indicator variable (IOR), a disposable parameter (beta) obtained by iteration, and a variable that parameterizes steric effects (MR) in the equation, log 1/Ki = 0.65 pi'3 - 1.22 log (beta X 10 pi'3 + 1) - 1.12IOR + 0.58MRY + 5.05 (r = 0.965). The EC50 values for triazine inhibition of L. major cell growth in culture are correlated by the equation log 1/EC50 = 0.21 pi 3 + 0.44 log 1/Ki + 0.53 (r = 0.960). When compared to DHFR from human, other vertebrates, and E. coli, L. major DHFR differs in that it optimally binds triazine congeners that are much more hydrophobic. Furthermore, in contrast to other DHFR's studied, triazine binding to L. major DHFR does not seem to be influenced by the electronic characteristics of the 3-X substituent of the parent triazine molecule. However, L. major DHFR is more sensitive to the steric effects and polarizability of the 3-X substituent. Our results indicate that triazines inhibit L. major promastigote growth via direct inhibition of DHFR as is shown by the good correlation between log 1/Ki values for inhibition of the purified enzyme and log 1/EC50 values for inhibition of cell culture growth. Two lipophilic, sterically large analogues of this triazine series showed selectivity for L. major DHFR over human DHFR. Further optimization of the MR and IOR terms in the above QSAR equations may provide even more selective inhibitors.

Folic Acid Antagonists↗

PubMed2002

Carbenoid reactions of 2-halomethyl-4,6-dimethyl-s-triazines.

Reactions of lithium, sodium, and potassium salts of 2,4,6-trimethyl-s-triazine (1) with 2-halomethyl-4,6-dimethyl-s-triazine (2) (X = Cl, Br) in glyme have been studied and found to give 1,2-bis(4,6-dimethyl-s-triazin-2-yl)ethane (3), 1,2-bis(4,6-dimethyl-s-triazin-2-yl)ethene (5), 1,2,3-tris(4,6-dimethyl-s-triazin-2-yl)cyclopropane (6), 1,2,3-tris(4,6-dimethyl-s-triazin-2-yl)propane (7), and 1,2,3,4-tetrakis(4,6-dimethyl-s-triazin-2-yl)butane (8). It is proposed that product 3 is formed primarily via an S(N)2 reaction, whereas the remaining products are formed primarily via carbenoid reactions that are enumerated.

Cyclization↗

PubMed1997

Triazine derivatives inhibit rat hepatocarcinogenesis but do not enhance gap junctional intercellular communication.

We report here novel candidate chemopreventive agents active against experimental hepatocarcinogenesis. The triazine derivatives 6-(2-chlorophenyl)-2,4-diamino-1,3,5-triazine (2CPDAT), 6-(3-chlorophenyl)-2,4-diamino-1,3,5-triazine (3CPDAT), 6-(4-chlorophenyl)-2,4-diamino-1,3,5-triazine (4CPDAT), 6-(4-pyridyl)-2,4-diamino-1,3,5-triazine (PyDAT), and 6-(pyridine N-oxid-4-yl)-2,4-diamino-1,3,5-triazine (PyNODAT), synthesized in our laboratory, in addition to 6-(2,5-dichloro-phenyl)-2,4-diamino-1,3,5-triazine (DCPDAT), or irsogladine, which is a widely used anti-ulcer drug, were investigated for potential chemopreventive effects in a rat liver medium-term bioassay system. A significant inhibitory influence on enzyme-altered liver foci was found for 2CPDAT, 3CPDAT, 4CPDAT, and PyNODAT, but not for DCPDAT or PyDAT. The involvement of gap junctional intercellular communication in the inhibition was studied, but no change in gap junctional intercellular communication capacity in rat liver cells in vitro or in gap junction protein (connexin 32) expression in rat liver in vivo was noted. These results indicate that, although these irsogladine analogues exert inhibitory effects on rat liver carcinogenesis, their action is independent of modification of gap junctional intercellular communication.

Animals↗

PubMedDate not supplied

Photosynthetic electron transport inhibition by 2-substituted 4-alkyl-6-benzylamino-1,3,5-triazines with thylakoids from wild-type and atrazine-resistant Chenopodium album.

The effect of 2-benzylamino-1,3,5-triazines on photosynthetic electron transport (PET) was measured with thylakoids isolated from atrazine-resistant, wild-type Chenopodium album, and spinach to find novel 1,3,5-triazine herbicides bearing a strong PET inhibition. The PET inhibition assay with Chenopodium (wild-type and resistant), yielded a resistance ratio (R/W = I50 (resistant)/I50 (wild-type)) of 324 for atrazine while for benzylamino-1,3,5-triazine derivatives of diamino-1,3,5-triazines a R/W of 11 to 160 was found. The compounds having a benzylamino group at one of the amino groups in the diamino-1,3,5-triazines have a resistant ratio down to one half to 1/30 of the atrazine value. The average resistance ratio of 21 benzylamino derivatives of monoamino-1,3,5-triazines was found to be about 4.0. The inhibition of 21 benzylamino-1,3,5-triazines assayed with atrazine-resistant Chenopodium thylakoids, indicated by pI50 (R)-values, correlated well with the PET inhibition pI50 (W) of wild-type thylakoids from Chenopodium.

Atrazine↗

PubMed1996

The inhibition of estrogen receptor-mediated responses by chloro-S-triazine-derived compounds is dependent on estradiol concentration in yeast.

The chloro-S-triazine derived compounds atrazine, atrazine desisopropyl, cyanazine, and simazine are commonly used herbicides. These compounds do not have estrogenic activity in yeast expressing human estrogen receptor (hER) and an estrogen-sensitive reporter. In the presence of a concentration of estradiol (20 nM) that induced maximal reporter activity in yeast, the triazines did not inhibit reporter activity. However, the triazines decreased reporter activity in a dose dependent manner in the presence of a submaximal concentration of estradiol (0.5 nM). The estradiol-dependent activity of a mutant hER lacking the amino terminus was not inhibited by the triazines in yeast. Competition binding assays demonstrated that the triazines displaced radiolabeled estradiol from recombinant hER. These results suggest that the ability of the triazines to inhibit estrogen receptor-mediated responses in yeast occur through their interaction with hER and is dependent on the concentration of estradiol.

Atrazine↗

PubMed1995

Synthesis and antiviral activity of benzyl-substituted imidazo [1,5-a]-1,3,5-triazine (5,8-diaza-7,9-dideazapurine) derivatives.

A variety of imidazo[1,5-a]-1,3,5-triazine derivatives carrying C-, O-, and S-benzyl and/or 4-methylbenzyl groups were synthesized and examined for their inhibitory effects on the replication of ortho- and paramyxoviruses. The key compounds 8-R-2-thioxo-2,3-dihydroimidazo [1,5-a]-1,3,5-triazin-4(1H)-ones 3a,b,d were synthesized by chlorotrimethylsilane/HMDS-effected cyclization--rearrangement of the corresponding 6-amino-5-(formylamino)-5-R-2-mercaptopyrimidin-4(5H)-ones 2a,b,d (R = benzyl, 4-methylbenzyl and 5-(benzyloxy)pentyl). Compounds 3a,b were further transformed into 4-thiones 5a,b and 4-dimethylamino derivatives 7a,b. Preparation of S-methyl, S-benzyl, and S-(4-methylbenzyl) derivatives 12-19 was carried out by the treatment of thioxo compounds 3b,d, 5b, and 8b in an alcohol/potassium carbonate system with methyl iodide or the appropriate aralkyl bromide. Simultaneous presence of the benzyl and thio structural units was found to be indispensable for any selective biological activity. Some 2-thio substituted compounds were specifically inhibitory to some viruses, e.g., 8-(4-methylbenzyl)-2-[(4-methylbenzyl) thio]imidazo[1,5-a]-1,3,5-triazin-4-one (13) and 8-[5-(benzyloxy)pentyl]-2-[(4-methylbenzyl)thio]imidazo [1,5-a]-1,3,5-triazin-4-one (15) inhibited influenza A virus at a concentration of 4.1 and 5.3 microM, and 2-(benzylthio)-6, 8-dimethylimidazo[1,5-a]-1,3,5-triazin-4-one (16) and 6, 8-dimethyl-2-[(4-methylbenzyl)thio]imidazo[1,5-a]1,3, 5-triazin-4-one (17) inhibited respiratory syncytial virus at a concentration of 21.9 and 15.7 microM, respectively, that is, at concentrations that were 20-50-fold lower than the cytotoxic concentrations. Compound 13 was inhibitory to respiratory syncytial virus at a concentration of 1.4 microM, that is, at a concentration that was 180-fold lower than the cytotoxic concentration to MDCK or Vero cells but only 7-fold lower than the cytotoxic concentration to HeLa cells. The 4-thiones 5a,b were nonselectively inhibitory to ortho-and paramyxoviruses at concentrations that coincided with their cytotoxic concentrations.

Animals↗

PubMed1979

Synthesis and antihypertensive activity of novel 3-hydrazino-5-phenyl-1,2,4-triazines.

In an effort to develop antihypertensive agents with peripheral vasodilator activity, a series of 40 novel 3-hydrazino-5-phenyl-1,2,4-triazines (II) were synthesized and evaluated in the spontaneously hypertensive rat assay (SHR assay). Based on the performance of the structurally related standard, hydralazine (I), 15 triazines were active. Thirteen of these hypotensive triazines possessed LD50 values in the mouse greater than I (LD50 = 100 mg/kg); only one active triazine had an LD50 value greater than 300 mg/kg (11d). Four asymmetric triazines had moderate antihypertensive activity and LD50 values greater than 300 mg/kg (6b, 7c, 8f, and 9g). Based on the relationship between toxicity and antihypertensive activity, three triazines (8f, 9g, and 11d) were chosen for dose-responses studies in the SHR assay. None were as efficacious as I, but all three were less toxic, resulting in similar therapeutic indices relative to I.

Animals↗

PubMed1982

Synthesis and enzymic activity of various substituted pyrazolo[1,5-a]-1,3,5-triazines as adenosine cyclic 3',5'-phosphate phosphodiesterase inhibitors.

A series of various pyrazolo[1,5-a]-1,3,5-triazines have been prepared and studied as inhibitors of cAMP phosphodiesterase isolated from bovine brain, bovine heart, and rabbit lung. A number of compounds were found to be superior to theophylline. 2-Ethyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine (35) was found to be 97 times more potent than theophylline as an inhibitor of bovine brain PDE. 8-Bromo-2,4-dimethyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine (52) showed alpha lung = 40 compared to alpha heart = 3.0. Thus, various substituents could increase or decrease the inhibition relative to the type and source of tissue from which the PDE was isolated. The most active compound was 8-bromo-4-(diethylamino)-7-phenylpyrazolo[1,3-a]-1,3,5-triazine (25), which was 185 times more potent than theophylline as an inhibitor of PDE isolated from rabbit lung. The stepwise synthesis via ring-closure procedures of requisite pyrazole intermediates, followed by electrophilic substitution in the pyrazole ring and/or nucleophilic substitution in the 1,3,5-triazine moiety, resulted in the various pyrazolo[1,5-a]1,3,5-triazines listed in Tables I and II. Structure-activity relationships are reviewed.

3',5'-Cyclic-AMP Phosphodiesterases↗