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PubMed2026

Triazole resistance in clinical Aspergillus fumigatus isolates in India, a multicenter surveillance study.

BACKGROUND: Triazole resistance in Aspergillus fumigatus is a global public health concern associated with treatment failure, notably in invasive aspergillosis. However, population-level data on triazole resistance from India remain limited, with most reports originating from single-center studies. METHODS: We conducted a multicenter surveillance study to assess the prevalence of triazole resistance among clinical A. fumigatus isolates across India. Antifungal susceptibility testing was performed using the CLSI broth microdilution method (M38-Ed3), and molecular characterization was conducted on resistant isolates. A total of 518 isolates were analyzed: 115 prospectively collected from 13 tertiary-care hospitals from 2015-2020, and 403 archived isolates obtained from the National Culture Collection of Pathogenic Fungi (1994-2020). RESULTS: The overall pooled prevalence of non-wildtype isolates was 4.1% for itraconazole (95% CI: 2.54-6.17%), 3.9% for posaconazole (95% CI: 2.39-5.94%), while 1.4% were resistant to voriconazole (95% CI: 0.55-2.77%). One multi-azole-resistant isolate from an immunocompromised, mold-active triazole-naïve patient carried the TR34/L98H mutation, suggesting environmental acquisition. Prevalence of resistance did not differ significantly across geographic regions or between public and private sector hospitals. Linear regression analysis revealed a significant temporal increase in median MICs of all three licensed triazoles between 1994 and 2020. Approximately 29% of isolates exhibited amphotericin B MICs exceeding the epidemiological cutoff value; however, the clinical significance of this finding remains uncertain. CONCLUSIONS: Azole resistance among clinical A. fumigatus isolates in India remains uncommon (<5%), supporting the continued use of triazoles as first-line therapy. However, the observed temporal increase in triazole MICs underscores the need for sustained national surveillance to detect emerging resistance trends.

Aspergillus fumigatus↗

PubMed2006

Gene expression profiling in the liver of CD-1 mice to characterize the hepatotoxicity of triazole fungicides.

Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR.

Animals↗

PubMedDate not supplied

Antifungal triazoles induce malformations in vitro.

Triazole-derivatives are antimycotics used in agriculture as well as in clinical and veterinary therapy. The aim of the present work is the in vitro comparative study of the teratogenic activity of triazole (the parental compound), flusilazole (an agricultural triazole mono-derivative fungicide), and fluconazole (a clinically used bis-triazole derivative). Rat embryos, 9.5 days old (1 to 3 somites) were exposed in vitro to triazole 500 to 5000 microM, flusilazole 3.125 to 250 microM, or fluconazole 62.5 to 500 microM. After 48 h in culture, the embryos were morphologically examined and processed for histologic and biochemical analysis. Flusilazole and fluconazole showed similar teratogenic effects (abnormalities at the branchial apparatus level and cell death at the level of the branchial mesenchyme) at concentration levels of 6.25 microM and higher for flusilazole and of 125 microM and higher for fluconazole. By contrast, only slight developmental retardation and blood discoloration were observed at the highest concentrations of triazole, suggesting no teratogenic activity for the triazole group.

Abnormalities, Drug-Induced↗

PubMed2002

[1,2,4]Triazole derivatives as 5-HT(1A) serotonin receptor ligands.

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.

Animals↗

PubMed1988

Triazolines. 14. 1,2,3-Triazolines and triazoles, a new class of anticonvulsants. Drug design and structure-activity relationships.

Pioneering studies in our laboratories have led to the emergence of the delta 2-1,2,3-triazolines (4,5-dihydro-1H-1,2,3-triazoles) and the closely related 1H-1,2,3-triazoles as a unique family of anticonvulsant agents hitherto unknown. Unlike the traditional anticonvulsants, the dicarboximide moiety is absent from the traiazoline ring system. This paper examines the results of evaluation of several groups of 1-aryl-5-pyridyl-substituted triazolines and triazoles with particular reference to structure-activity relationships in each compound group as well as between compounds in the different groups and the 1,5-diaryl compounds. The Topliss manual approach for application fo the Hansch method is employed for the rational design of triazoline/triazole anticonvulsants. Anticonvulsant activity was determined, after intraperitoneal administration, in two standard seizure models in the mouse, the MES and scMet tests. Central nervous system toxicity was evaluated in the rotorod ataxia test. Analysis of structure-activity relationships using the Topliss scheme indicated a clear pi + sigma dependency in the 1-aryl-5-(4-pyridyl)triazolines while an adverse steric effect (Es) from 4-substitution appeared to be present in the 1-aryl-5-(3-pyridyl) compounds. A similar but strong steric effect dominated the structure-activity pattern of the 1-aryl-5-(4-pyridyl)triazoles, although a sigma dependency was more evident in the 1-aryl-5-(3-pyridyl)- and the 1,5-diaryltriazole series. No significant activity was observed among the 1-aryl-5-(2-pyridyl)triazolines, and although the respective triazoles were active, the parameter dependency was not clearly defined. Similarly, the 1,5-diaryltriazolines, as a group, showed no pronounced anticonvulsant activity. However, replacement of the 5-aryl with a pyridyl group, particularly a 4-pyridyl, led to highly enhanced anticonvulsant activity. In addition, oxidation of triazolines with no anticonvulsant activity yielded, as a rule, triazoles that were active, which could be linked to their chemistry or structural conformation. The triazolines and triazoles evince anticonvulsant activity as a class and compare very well with the prototype antiepileptic drugs--ethosuximide, phenytoin, phenobarbital, valproate--in their anticonvulsant potency and minimal neurotoxicity. They have emerged as a new generation of anticonvulsant agents that show great promise as potentially useful antiepileptic drugs.

Animals↗

PubMed2006

Impact of changes in the target P450 CYP51 enzyme associated with altered triazole-sensitivity in fungal pathogens of cereal crops.

Control of diseases caused by fungi in both medicine and agriculture is heavily dependent on the use of triazoles. As a consequence, resistance to triazoles is a threat to both human health and the sustainability of agricultural production systems. In human pathogens, particularly Candida albicans, mutations encoding alterations in the target cytochrome P450 sterol 14alpha-demethylase (CYP51; where CYP is cytochrome P450) enzyme are the primary determinants of triazole resistance. In fungal pathogens of cereals, CYP51A1 modifications, some at positions known to contribute to a resistant phenotype in human pathogens, have also been identified in isolates with altered triazole-sensitivity. However, unlike medicine where resistance to triazoles is a major clinical problem, failures of triazoles to control crop diseases in the field are rare with mean population sensitivities generally remaining low, perhaps due to differences in the selection pressures imposed on human and cereal pathogen populations. Nonetheless, the biological potential for resistance exists, and the question remains as to whether widespread triazole resistance can develop in an important cereal pathogen.

Cytochrome P-450 Enzyme System↗

PubMed1991

[Studies on reaction and antibacterial activity of 1-aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazole with several electrophilic reagents].

Upon treatment of 1-aryl-4-ethoxycarbonyl-5-amino-1,2,3-triazoles (1) with excess acetic acid, acetic anhydride, acetyl chloride, benzoyl chloride, formamide, etc., fourteen new derivatives of 1 were obtained in good yields, such as, 1-H-4-ethoxycarbonyl-5-arylamino-1,2,3-triazoles (2b-d), 1-RCO-4-ethoxycarbonyl-5-arylamino-1,2,3-triazoles (3a-d), 1-aryl-4-ethoxycarbonyl-5-acetylamino-1,2,3-triazoles (4a-d) and 1-formoyl-4-ethoxycarbonyl-5-p-nitrophenylamino-1,2,3-triazole (5a), 1-benzoyl-4-ethoxycarbonyl-5-p-nitrophenylamino-1,2,3-triazoles (5b), 1-p-chlorobenzoyl-4-ethoxycarbonyl-5-p-nitrophenylamino-1,2,3-triazoles (5c). Some of them were rearrangement products. Structures of all heterocyclic compounds were identified by elemental analyses, IR, 1HNMR and MS. Inhibiting effects of some compounds on B. substilis, E. coli, E. aerogenes and S. aureus were also screened.

Anti-Bacterial Agents↗

PubMed2005

Syntheses, structures, and magnetic properties of unusual nonlinear polynuclear copper(II) complexes containing derivatives of 1,2,4-triazole and pivalate ligands.

Novel polynuclear Cu(II) complexes containing derivatives of 1,2,4-trizaole and pivalate ligands, [Cu(3)(mu(3)-OH)(mu-adetrz)(2)(piv)(5)(H(2)O)].6.5H(2)O (1) (adetrz = 4-amino-3,5-diethyl-1,2,4-triazole, piv = pivalate), [Cu(4)(mu(3)-OH)(2)(mu-atrz)(2)(mu-piv)(4)(piv)(2)].2MeOH.H(2)O (2) (atrz = 4-amino-1,2,4-triazole), [Cu(4)(mu(3)-OH)(2)(mu-tbtrz)(2)(mu-piv)(2)(piv)(4)].4H(2)O (3) (tbtrz = 4-tert-butyl-1,2,4-trizaole), and [Cu(4)(mu(3)-O)(2)(mu-admtrz)(4)(admtrz)(2)(mu-piv)(2)(piv)(2)].2[Cu(2)(mu-H(2)O)(mu-admtrz)(piv)(4)].13H(2)O [4 = 4a.2(4b).13H(2)O; admtrz = 4-amino-3,5-dimethyl-1,2,4-triazole], have been prepared and structurally characterized. 1 is an asymmetrical triangular complex containing a [Cu(3)(mu(3)-OH)] core with two Cu---Cu edges spanned by bridging adetrz ligands. 2, 3, and 4a are novel tetranuclear compounds containing a [Cu(4)(mu(3)-O)(2)] or [Cu(4)(mu(3)-OH)(2)] core with Cu---Cu edges spanned by bridging 1,2,4-triazole or pivalate ligands. 4b is a dinuclear compound with one admtrz and one water bridge, and it is the first dinuclear Cu(II) triazole complex with one bridging water molecule. 1 is one of few reported triangular Cu(II) complexes with derivatives of 1,2,4-triazole, while 2, 3, and 4a are the first group of the nonlinear tetranuclear Cu(II) compounds with derivatives of 1,2,4-triazole. Variable-temperature magnetic susceptibility studies on the powder samples of 1-3 reveal the overall antiferromagnetic coupling between Cu(II) ions with J values of -55.6 to -12.8 cm(-1) (1), -216.4 to 0 cm(-1) (2), and -259.8 to 4.8 cm(-1) (3).

Journal Article↗

PubMed2005

Copper(I) 1,2,4-triazolates and related complexes: studies of the solvothermal ligand reactions, network topologies, and photoluminescence properties.

One-pot solvothermal treatments of organonitriles, ammonia, and Cu(II) salts yielded Cu(I) and 3,5-disubstituted 1,2,4-triazolates. The organic triazolate components were derived from copper-mediated oxidative cycloaddition of nitriles and ammonia, in which a key intermediate 1,3,5-triazapentadienate was isolated as [Cu(II)(4-pytap)(2)] (4-Hpytap = 2,4-di(4-pyridyl)-1,3,5-triazapentadiene) via controlled solvothermal conditions. This intermediate could also be synthesized by Ni(II)-mediated reactions; however, the final triazoles were obtained only when Cu(II) was employed. Therefore, the reaction mechanism of these reactions was elucidated as follows: nitrile was first attacked by ammonia to form the amidine, which further reacted with another nitrile or self-condensed to yield 1,3,5-triazapentadiene, which was coordinated to two Cu(II) ions in its deprotonated form. A two-electron oxidation of the 1,3,5-triazapentadienate mediated by two Cu(II) ions gave one triazolate and Cu(I) cations. Other in situ ligand reactions, such as C-C bond cleavage and hydrolysis, were also found for the nitriles under these solvothermal conditions. Another remarkable feature of these crystalline Cu(I) triazolates is their simple, typical 3- or 4-connected network topologies. The self-assembly of these nets is presumably controlled by steric hindrance, which is subsequently applied to the rational design of the close-packed 2D networks [Cu(I)(tz)](infinity) and [Ag(I)(tz)](infinity) (Htz = 1,2,4-triazole), as well as the porous 3D network [Cu(I)(etz)](infinity) (Hetz = 3,5-diethyl-1,2,4-triazole). The interesting photoluminescence properties of these coinage d(10) metal complexes were also investigated.

Journal Article↗

PubMed2006

Synthesis and CYP26A1 inhibitory activity of 1-[benzofuran-2-yl-(4-alkyl/aryl-phenyl)-methyl]-1H-triazoles.

Methodology previously described by our group was applied to the preparation of a series of 4-alkyl/aryl-substituted 1-[benzofuran-2-yl-phenylmethyl]-1H-triazoles. The [1,2,4]-triazole derivatives were prepared for a range of alkyl and aryl substituents, and for the 4-methyl, 4-ethyl, 4-(i)propyl, 4-(t)butyl, 4-phenyl and 4-chlorophenyl derivatives, the minor [1,3,4]-triazole isomer also isolated. All the triazole derivatives were evaluated for CYP26A1 inhibitory activity using a MCF-7 cell-based assay. The 4-ethyl and 4-phenyl-1,2,4-triazole derivatives displayed inhibitory activity (IC(50) 4.5 and 7 microM, respectively) comparable with that of the CYP26 inhibitor liarozole (IC(50) 7 microM). Using a CYP26A1 homology model (based on CYP3A4) template, docking experiments were performed with MOE with multiple hydrophobic interactions observed in addition to coordination between the triazole nitrogen and the haem transition metal.

Benzofurans↗

PubMed2005

Synthesis, characterization and antimicrobial activity of some substituted 1,2,3-triazoles.

Two substituted 1,2,3-triazoles 4 and 6 have been synthesized by the 1,3-dipolar cycloaddition reaction of 4-azido-8-(trifluoromethyl)quinoline 2 with ethyl acetoacetate and acetylacetone, respectively. The reaction of 2 with ethyl acetoacetate afforded 1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid 3 and with acetylacetone afforded 1-{1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazol-4-yl}ethanone 5. Compound 3 is converted into its corresponding acid hydrazide and then condensed with different aromatic aldehydes to yield Schiff's base, N-[1-arylmethylene]-1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazole-4-carbohydrazides 4. Compound 5 is condensed with aromatic aldehydes to obtain [1-aryl-4-{1-[8-(trifluoromethyl)quinolin-4-yl]-5-methyl-1H-1,2,3-triazol-4-yl}prop-2-en-1-ones 6. The newly prepared 1,2,3-triazole derivatives 4 and 6 have been characterized by IR, NMR and mass spectral data. These compounds were screened for their antimicrobial activity.

Anti-Bacterial Agents↗

PubMed2003

The development of new triazole based inhibitors of tumor necrosis factor-alpha (TNF-alpha) production.

4-Aryl-5-pyridyl and 4-aryl-5-pyrimidyl based inhibitors of TNF-alpha production, which contain a novel triazole 5-member heterocyclic core, are described. Many pyridyl triazoles containing either an alkyl ether or a substituted aryl side chain on the triazole core showed sub-micromolar activity against LPS-induced TNF-alpha, while pyrimidyl triazoles containing an ethoxymethyl side chain exhibited even better inhibitory activity. Secondary screening data are presented for the pyrimidyl triazoles. Triazole 14e combined excellent potency with good oral bioavailability in the rat.

Administration, Oral↗

PubMed2006

Synthesis and structure-activity relationships of 1-phenyl-1H-1,2,3-triazoles as selective insect GABA receptor antagonists.

To study the interaction of phenylheterocycles with gamma-aminobutyric acid (GABA) receptors, 4- or 5-alkyl(or phenyl)-1-phenyl-1H-1,2,3-triazoles were synthesized and examined for their ability to inhibit the specific binding of [3H]-4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a noncompetitive antagonist, to the housefly and rat GABA receptors, as well as to the beta3 subunit homo-oligomer of the human GABA receptor investigated as a model receptor. 4-Substituted 1-phenyl-1H-1,2,3-triazoles were found to be more potent competitive inhibitors than the 5-substituted regioisomers in the case of all receptors. The 4-tert-butyl or 4-n-propyl analogue of 1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazole exhibited the highest level of inhibition of [3H]EBOB binding to all receptors. Most of the synthesized analogues were more active in terms of the inhibition of EBOB binding to the housefly and human beta3 GABA receptors than to the rat receptor. The 4-cyclohexyl analogue showed the highest (185-fold) housefly versus rat receptor selectivity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis demonstrated that both the 4-trifluoromethyl-2,6-dichloro substitution on the phenyl ring and a small, bulky, hydrophobic substituent at the 4-position of the triazole ring played significant roles in conferring high potency in cases involving the housefly and human beta3 receptors. The human beta3 receptor resembled the housefly receptor in terms of their recognition of phenyltriazoles, whereas 3D-QSAR analysis revealed a slight difference between the two receptors in terms of their mechanisms of recognition of the para-substituent on the phenyl moiety. Some of the triazoles synthesized here exhibited insecticidal activity, which was correlated with their ability to inhibit [3H]EBOB binding to the housefly receptor. Thus, 1-phenyl-1H-1,2,3-triazoles with the appropriate substituents exert insecticidal activity by selectively acting at the site for noncompetitive antagonism of insect GABA receptors.

Amino Acid Sequence↗

PubMedDate not supplied

Molecular recognition between oligopeptides and nucleic acids: DNA binding selectivity of a series of 1,2,4-triazole-containing lexitropsins.

The synthesis of a series of 1,2,4-triazole-containing oligopeptide lexitropsins related to the natural antitumor antibiotic distamycin is described. The binding properties of these new agents to both native DNAs and synthetic polydeoxyribonucleotides were determined by UV absorption and circular dichroism studies. The DNA binding and sequence selectivity of these agents have been determined by complementary strand MPE footprinting on two restriction fragments of pBR322 DNA. The lexitropsins bearing one 1,2,4-triazole moiety bind to AT sequences like distamycin but also tolerate GC sites. However, 3, which contains two contiguous 1,2,4-triazole moieties, appears not to recognize AT stretches and demands two consecutive GC bases in the middle of a four-base recognition site. The triazole lexitropsins avoid ATTT (4264-4267) and AAAA (4273-4276) to which distamycin binds strongly to the EcoRI/Hind III fragment. Determination of pKa values indicates the 1,2,4-triazole units are protonated under physiological conditions. The avoidance of AT stretches and the recognition of GC base sites by 3 suggest molecular recognition in these cases is determined, not by electrostatic effects, but rather by invoking a hydrogen bond between the triazole 4-nitrogen and G-2NH2 in the minor groove.

Base Sequence↗

PubMed2006

Disruption of testosterone homeostasis as a mode of action for the reproductive toxicity of triazole fungicides in the male rat.

Triazole fungicides associated with a range of reported male reproductive effects in experimental animals were selected to assess potential toxic modes of action. Wistar Han rats were fed myclobutanil (M: 100, 500, or 2000 ppm), propiconazole (P: 100, 500, or 2500 ppm), or triadimefon (T: 100, 500, or 1800 ppm) from gestation day 6 to postnatal day (PND) 120. One male per litter was necropsied on PND1, 22, 50, or 92. Measurements included anogenital distance (AGD) at PND0, body and organ weights, serum hormone levels, age at preputial separation (PPS), sperm morphology and motility, and fertility and fecundity. AGD was increased by the high dose of all three triazoles, indicating hypervirilization. Triadimefon delayed PPS, consistent with delayed puberty, at 1800 ppm. Relative liver weights were increased at PND1, 50, and 92 by all three triazoles. Hepatocellular hypertrophy was present at PND50 from propiconazole and triadimefon and at PND92 from all three high-dose triazole treatments. Relative pituitary weights were decreased at PND92 by middle- and high-dose myclobutanil treatment. Absolute testis weights were increased at PND1 by myclobutanil, at PND22 by myclobutanil and triadimefon, and at PND50 by propiconazole and triadimefon treatment. Relative ventral prostate weights were increased at PND92 by myclobutanil and triadimefon treatment. Serum testosterone was increased at PND50 by triadimefon and at PND92/99 by all three triazole treatments. Insemination and fertility were impaired by myclobutanil and triadimefon treatment. In addition to the reproductive system effects, total serum thyroxine levels were decreased at PND92 by high-dose triadimefon. These reproductive effects are consistent with the disruption of testosterone homeostasis as a key event in the mode of action for triazole-induced reproductive toxicity.

Anal Canal↗

PubMed2001

Synthesis of 3-(3,4-dimethoxyphenyl)-1 H-1,2,4-triazole-5-thiol and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibiting anti-inflammatory activity.

New 1-acylderivatives of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazole (5c-f, 6d-f) were synthesized by the acylation of 5-alkylthio-3-(3,4-dimethoxyphenyl)-4H-1,2,4-triazoles (3, 4) with acyl chlorides. The compounds 3, 4 were obtained by the alkylation of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol (2) sodium salt with alkyl iodides. Compound 2 and 2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole (8) were prepared by the treatment of 3,4-dimethoxybenzoylthiosemicarbazide (1) with sodium hydroxide or acetyl chloride (and then sodium hydroxide), respectively. Related 2-acylamino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazoles (7c, e, f) were synthesized by the acylation of compound 8 with acyl chlorides. 3-(3,4-Dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thione (9) was N-acylated with acyl chlorides or S-methylated with iodomethane to give 1-acyl-3-(3,4-dimethoxyphenyl)-4-phenyl-4,5-dihydro-1H- 1,2,4-triazole-5-thiones (10a, b) or 3-(3,4-dimethoxyphenyl)-5-methylthio-4-phenyl-4H-1,2,4-triazole (11) respectively. The synthesized compounds 6d, 7a, c, 10a, b, 11 exhibit anti-inflammatory activity.

Animals↗

PubMed2003

In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature.

The echinocandins anidulafungin and micafungin and the triazole posaconazole are currently undergoing phase III clinical trials. Caspofungin and voriconazole have recently been licensed for the treatment of aspergillosis (both agents), other less common mould (voriconazole) and candidal (caspofungin) infections. This review summarizes the published in vitro data obtained by NCCLS or NCCLS modified methods on the in vitro fungistatic and fungicidal activities of these five agents for yeasts and moulds in comparison to the established agents, amphotericin B, fluconazole, itraconazole, and flucytosine. Among the yeasts, the echinocandins have less activity for Candida parapsilosis and Candida guilliermondii, no activity for Cryptococcus neoformans and Trichosporon spp., but good fungistatic and fungicidal activity in vivo and in vitro for most of the other Candida spp.; this fungicidal activity has been reported by minimum fungicidal concentrations (MFCs) or time kill curve results. The new triazoles exhibit good fungistatic activity (but not fungicidal) for most Candida spp., C. neoformans, and Trichosporon spp. For the Aspergillus spp. evaluated, the echinocandins have similar or better fungistatic activity than those of amphotericin B and the triazoles, but fungicidal activity has been demonstrated only with amphotericin B and the triazoles, with the exception of fluconazole. Most studies showed posaconazole and voriconazole minimum inhibitory concentrations (MICs) ranging from 0.25 to 8 microg/ml for non-solani Fusarium spp., while MIC and minimum effective concentration (MEC) endpoints of the echinocandins were >8 microg/ml. The fungistatic activity of the triazoles is also superior to that of the echinocandins for most of the dimorphic fungi and the Zygomycetes. However, micafungin has activity for the mould phase of most dimorphic fungi, but not for the parasitic or yeast phase of Paracoccidioides brasiliensis. The echinocandins appear to have variable and species dependent fungistatic activity for the dematiaceous fungi, but all agents have poor or no activity against most isolates of Scedosporium prolificans. Only amphotericin B exhibit good fungistatic activity against the Zygomycetes. The combination of caspofungin with some triazoles, amphotericin B or liposomal amphotericin B has been synergistic in vitro, in animal models and in patients. Breakpoints are not available for any mould and antifungal agent combination. In vitro/in vivo correlations should aid in the interpretation of these results, but standard testing conditions are needed for the echinocandins, especially for mould testing, to obtain reliable results.

Anidulafungin↗

PubMedDate not supplied

Determination of 22 triazole compounds including parent fungicides and metabolites in apples, peaches, flour, and water by liquid chromatography/tandem mass spectrometry.

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed for the determination of 14 parent triazole fungicides and 8 of their metabolites found in apples, peaches, flour, raw water, and tap water. The triazole fungicides chosen for this multiresidue method development project included propiconazole, fenbuconazole and its RH-9129 and RH-9130 metabolites, cyproconazole, difenoconazole, tebuconazole and its HWG 2061 metabolite, hexaconazole, bromuconazole (both stereoisomers), epoxiconazole, tetraconazole, triticonazole and its RPA-404886 and RPA-406341 metabolites, triadimefon, triadimenol, and myclobutanil. Of special concern to the U.S. Environmental Protection Agency were the metabolites common to all triazole fungicides: free triazole, 1,2,4-triazole (T), and its 2 conjugates: triazolylalanine (TA) and triazolylacetic acid (TAA). These metabolites were the primary focus of this project. All samples we cleaned up by a combination of C18 solid-phase extraction (SPE), mixed-mode cationic SPE, and mixed-mode anionic SPE columns. A triple-stage quadrupole mass spectrometer, equipped with electrospray ionization in the positive-ion mode, was used to determine the compounds of interest. T, TA, and TAA were quantitated using isotopically labeled internal standards (IS), in which the 1,2,4-triazole ring had been synthesized by using 13C and 15N (IS_T, IS_TA, and IS_TAA). These isotopically labeled internal standards were necessary to correct for matrix effects. The T, TA, and TAA metabolites were quantitated at the 25-50 parts-per-billion (ppb) level in food commodities and at 0.50 ppb in water. Recoveries were 70-101% from apples, 60-121% from peaches, 57-118% from flour, 75-99% from raw water, and 79-99% from tap water.

Calibration↗