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[Reactivity of 3-aryl-4-amino-5-mercapto-4H-1,2,4-triazoles: synthesis and biological evaluation of 3,6-diaryl derivatives of 7H-1,2,4-thiazole[3,4-b][1,3,4]thiadiazines, of 3-aryl-4-amino-5-carboxymethylthio-4H-1,2,4-triazoles].

Starting from 3-aryl-4-amino-5-mercapto-4H-1,2,4-triazoles (II), two series of 3,6-disubstituted 7H-1,2,4-triazol [3,4-b] [1,3,4] thiadiazines (III) and their 5-carboxymethylthio derivatives (IV) were prepared. From the mercapto-amino-triazoles (II) because of their reactivity in some oxidising media, were obtained the triazole derivatives (V), (VI) and (VII). The synthesis of the alpha-thioketones (VIII) of 3-aryl-5-mercapto-1,3,4-oxadiazoles (I), used in alternative synthesis of triazole-thiadiazines (III), is also reported. All the substances described were subjected to biological screening. In the tests, the carboxymethylthiotriazole (IV) showed weak antiinflammatory activity (carrageenin edema) and more consistent scavanger activity, in vitro, on superoxide anions. The triazole-thiadiazines (III) and triazoles (II), (V) and (VI) showed moderate antimycotic activity.

Analgesics

Structures of the anticancer compounds N-(2-hydroxyethyl)-2-(3-nitro-1,2,4-triazol-1-yl)-acetamide (RB-6110) and 5-(1-aziridinyl)-3-nitro-1-(3-oxo-1-butyl)-1,2,4- triazole (RB-6162).

RB-6110: C6H9N5O4, Mr = 215.17, monoclinic, C2/c, a = 20.595 (3), b = 4.713 (1), c = 19.914 (4) A, beta = 110.69 (1) degree, V = 1808.3 A3, Z = 8, Dx = 1.588 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.838 mm-1, F(000) = 675, T = 298 K, final R = 0.042 for 1219 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6162: C8H11N5O3, Mr = 225.21, monoclinic, P2(1)/c, a = 7.515 (1), b = 14.758 (2), c = 9.813 (1) A, beta = 108.49 (1) degree, V = 1032.1 A3, Z = 4, Dx = 1.450 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.927 mm-1, F(000) = 472, T = 298 K, final R = 0.042 for 1113 observed reflections with I greater than or equal to 1.5 sigma (I). RB-6110 and RB-6162 are 3-nitro-1,2,4-triazoles with potential application as anticancer agents. The nitro groups are in the plane of the aromatic triazole ring with dihedral angles of 1.2 (4) and 4.6 (4) degrees, respectively. The arizidine substituent of RB-6162 is almost perpendicular [dihedral angle 80.1 (4) degrees] to the triazole plane. Molecular-orbital calculations on RB-6162 have confirmed that this geometry is energetically favoured. The energy barrier to rotation about the triazole-aziridine bond has been determined as 51.5 (5) kJ mol-1 by the dynamic NMR method.

Antineoplastic Agents

s-triazole systems. Part IV: Novel substituted thio-s-triazole derivatives.

Interaction of (3-aryloxymethyl-4-phenyl-s-triazol-5-yl)thioacethydrazid e (1a-c) with phenyl isocyanate and/or with methyl/phenyl isothiocyanate gave semicarbazides (2a-c) and thiosemicarbazides (3a-f) respectively. Cyclization of (3a-f) yielded s-triazoles (4a-f). Compounds 4b,d,f were easily alkylated giving S-substituted thio-s-triazoles (5a-e). Furthermore, compounds 4b,d,f underwent a Mannich reaction to give the expected Mannich bases (6a-f). All compounds were fully confirmed by elemental and spectral analyses and have been screened in vitro for antimicrobial activity.

Anti-Bacterial Agents

Synthesis and anti-human immunodeficiency virus (HIV-1) activity of 3'-deoxy-3'-(triazol-1-yl)thymidines and 2',3'-dideoxy-3'-(triazol-1-yl)uridines and inhibition of reverse transcriptase by their 5'-triphosphates.

3'-Deoxy-3'-(1,2,3-triazol-1-yl)thymidines (5a, 6a, 8a, 11a, and 12a) and 2',3'-dideoxy-3'-(1,2,3-triazol-1-yl)uridines (5b, 6b, 8b, 11b, and 12b) were synthesized as cyclic analogues of 3'-azido-3'-deoxythymidine (AZT) and 3'-azido-2',3'-dideoxyuridine (CS-87) by the cyclization of 5'-trityl derivatives (1a, b) of AZT and CS-87 using alpha-ketophosphorus ylides and with acetylenic compounds followed by deprotection of the 5'-trityl group. It was hypothesized that the triazole nitrogen atoms could mimic and distorted azido group. However, no significant activity against human immunodeficiency virus type 1 (HIV-1) was observed with any of these compounds. 5'-Triphosphates (17a and 18a, b), prepared from 5a and 6a, b, were inactive against HIV-1 and Rauscher murine leukemia virus (RLV) reverse transcriptases.

Acquired Immunodeficiency Syndrome

Potential antihypertensives. Synthesis of 6-substituted-N-(4H-1,2,4-triazol-4-yl)-3-pyridazinamines and 3-substituted-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazines.

A series of 6-substituted-N-(4H-1,2,4-triazol-4-yl)-3-pyridazinamines [(II), Scheme 1] and 3-substituted-6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl) pyridazines [(XII), Scheme 3-5] were synthesized. The compounds were evaluated for their oral antihypertensive activity in rats (SHR) and only some compounds of structure (XII) induced a moderate decrease in systolic blood pressure.

Animals

Studies on 1,2,3-triazoles. 13. (Piperazinylalkoxy) [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-ones with combined H1-antihistamine and mast cell stabilizing properties.

Several N-benzylpiperazino derivatives of [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-one and its 5-methyl homologue have been prepared and evaluated for H1-antihistamine activity on guinea pig ileum. The most potent compounds were also evaluated for their ability to stabilize mast cells in the rat passive peritoneal anaphylaxis (PPA) system and were shown to inhibit histamine release at concentrations below those required to inhibit extravasation, suggesting that this might be relevant to their antianaphylactic activity in this system. The compound tested with the most potent H1-antihistamine activity was 6-[3-[4-(4-chlorobenzyl)-1-piperazinyl]propoxy][1]benzopyrano[2,3- d]-1,2,3-triazol-9(1H)-one, 28, which had a pA2 of 9.1 against histamine on guinea pig ileum, comparable to that of mepyramine, and inhibited histamine release in the rat PPA system with an IC50 value of 5.4 X 10(-6) M.

Anaphylaxis

4(H)-1,2,4-triazole derivatives with expected biological activity. Part IV. Synthesis of substituted 3,4,5-triaryl-1,2,4-triazoles.

A series of 23 3,4,5-triaryl-1,2,4-triazoles with various substituents in one, two, or all three aromatic rings were prepared for screening tests as potential antibacterial, mostly antituberculotic agents. The synthesis, depending on the nature and position of the substituents, was accomplished by one of the following methods; (A) condensation of symmetrically substituted bis(alpha-chlorobenzylidene)hydrazine with an aniline derivative; (B) reaction of an aniline derivative with a symmetrical diaroylhydrazine in the presence of PCL3; (C) direct condensation of aroylhydrazine with an appropriately substituted N-phenylbenzimidoyl chloride. The latter method was considered to be most advantageous; it warranted highest yield and purity of the products and made it possible to prepare triazoles with three different aryl groups.

Aniline Compounds

1,2,4-Triazole amino nucleosides. 1-beta-D-3'-Amino-3'-deoxyribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides.

The synthesis of 1-beta-D-3'-amino-3'-deoxyribofuranosyl-1,2,4-triazole-3-carboxamide--the 3'-amino analogue of ribavirin--and five related nucleoside analogues is described. Each analogue exhibited LD50 concentrations greater than 100 microgram/mL against P-388 mouse lymphoid leukemia cells in tissue culture. Antiviral testing indicated that none of the compounds exhibited significant activity.

Animals

Triazole-resistant Aspergillus fumigatus in the Netherlands between 1994 and 2022: a genomic and phenotypic study.

BACKGROUND: Aspergillus fumigatus is the main cause of invasive aspergillosis and triazole antifungals are the primary treatment option. The effectiveness of triazole therapy is hampered by the emergence of resistance, mainly caused by mutations in the cyp51A gene and a tandem repeat (TR) of 34 bases (TR34/Leu98His) and 46 bases (TR46/Tyr121Phe/Thr289Ala) in the promoter region, which correspond with signature triazole resistance phenotypes. We aimed to investigate the occurrence of triazole phenotype and genotype variation over a 29-year period in the Netherlands. METHODS: In this genomic and phenotypic study, we screened all clinical A fumigatus isolates from Dutch hospitals collected between Jan 6, 1994, and Dec 31, 2022, for resistance to triazole using agar-based methods, and characterised them by sequencing the cyp51A gene and in vitro susceptibility testing using the European Committee on Antimicrobial Susceptibility Testing reference method. Whole-genome sequencing was performed on selected isolates, including those harboring TR34 variants, high-frequency single-nucleotide polymorphisms, and wild-type strains. Clinical information such as age, underlying disease, diagnosis, therapy, and outcomes was collected for patients who had isolates cultured at the Radboud University Medical Centre, Nijmegen, Netherlands, between Jan 1, 2017, and Dec 31, 2022. FINDINGS: 1979 (15&#xb7;6%) of the screened 12&#x2009;679 A fumigatus isolates harboured cyp51A triazole resistance mutations, predominately TR34/Leu98His sensu stricto in 1338 (67&#xb7;6%) resistant isolates and TR46/Tyr121Phe/Thr289Ala sensu stricto in 332 (16&#xb7;8%) resistant isolates. Phenotype and genotype variations were observed in 325 (17&#xb7;2%) triazole resistant isolates harbouring a TR-resistance mechanism, including 12 cyp51A genotype variants. Whole-genome sequencing showed that isolates with combinations of TR34-based and TR46-based polymorphisms seemed to be derived from separate populations, but there was some overlap. 59 cases of proven or probable invasive aspergillosis were identified, including 13 triazole-resistant cases, of which three were caused by genotype variants. Mixed genotype infection was observed in 11 (84&#xb7;6%) of 13 triazole-resistant patients and the number of antifungal treatment switches was higher compared with triazole-susceptible disease (p<0&#xb7;0001). INTERPRETATION: Our study showed variation in triazole genotypes and phenotypes in clinical A fumigatus isolates with cyp51A-mediated resistance, some of which were cultured from triazole-resistant invasive aspergillosis cases. Triazole resistance variation and mixed A fumigatus genotypes represent a major challenge in clinical management of Aspergillus diseases because current molecular diagnostic tools will increasingly fail to predict the resistance phenotype, underscoring the need for improved detection methods. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China, and Wellcome Trust.

Aspergillus fumigatus

Synthesis and evaluation of 5-amino-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine and certain related nucleosides as inhibitors of purine nucleoside phosphorylase.

The 5-amino and certain related derivatives of the powerful purine nucleoside phosphorylase (PNPase) inhibitor 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (TCNR,3) have been prepared and evaluated for their PNPase activity. Acetylation followed by dehydration of 5-chloro-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide (4a) gave 5-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-1,2,4-triazole-3- carbonitrile (5). Ammonolysis of 5 furnished 5-amino-1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamidine (5-amino-TCNR, 6), the structure of which was assigned by single-crystal X-ray analysis. Acid-catalyzed fusion of methyl 5-chloro-1,2,4-triazole-3-carboxylate (7a) with 5-deoxy-1,2,3-tri-O-acetyl-D-ribofuranose (8) gave methyl 5-chloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)- 1,2,4-triazole-3-carboxylate (9a) and the corresponding positional isomer 9b. Transformation of the functional groups in 9a afforded a route to 5'-deoxyribavirin (9i). Compound 9a was converted in four steps to 5-amino-1-(5-deoxy-beta-D-ribofuranosyl)-1,2,4-triazole-3- carboxamidine (5'-deoxy-5-amino-TCNR, 9g). Similar acid-catalyzed fusion of 1,2,4-triazole-3-carbonitrile (7b) with 8 and ammonolysis of the reaction product 9h gave yet another route to 9i. Treatment of 9h with NH3/NH4Cl furnished 1-(5-deoxy-beta-D-ribofuranosyl)- 1,2,4-triazole-3-carboxamidine (5'-deoxy-TCNR, 9k). The C-nucleoside congener of TCNR (3-beta-D-ribofuranosyl- 1,2,4-triazole-5-carboxamidine, 12) was prepared in two steps from 3-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)- 1,2,4-triazole-5-carbonitrile (10) by conventional procedure. 5-Amino-TCNR (6) displayed a more potent, high-affinity inhibition than TCNR, with a Ki of 10 microM. In contrast, 5'-deoxy-5-amino-TCNR (9g) was a significantly less potent inhibitor of PNPase, compared to 5'-deoxy-TCNR (Ki = 80 and 20 microM, respectively). Neither the C-nucleoside congener of TCNR (12) nor that of ribavirin were found to inhibit inosine phosphorolysis.

Nucleosides

Studies on the mechanism of inhibition of Salmonella typhimurium by 1,2,4-triazole.

The inhibition of Salmonella typhimurium by 1,2,4-triazole appears to be mediated through an effect on L-cysteine biosynthesis. O-Acetylserine sulfhydrylase A, the final enzyme in the L-cysteine biosynthetic pathway, was found to catalyze a reaction (triazolylase) between O-acetyl-L-serine and 1,2,4-triazole, giving 1,2,4-triazole-1-alanine as a product. In wild type S. typhimurium grown on 4 mM 1,2,4-triazole, 97% of the total O-acetyl-L-serine synthesized in vivo is incorporated into 1,2,4-triazole-1-alanine. 1,2,4-triazole also significantly lowers the levels of several of the enzymes necessary for sulfate reduction. This effect is presumably due to the ability of the inhibitor to lower intracellular concentrations of O-acetyl-L-serine, an inducer of these enzymes. Inhibition of growth is probably caused by L-cysteine starvation, arising from the decreased availability of the L-cysteine precursors, sulfide and O-acetyl-L-serine. Two 1,2,4-triazole-resistant strains bearing mutations in cysK, the structural gene for O-acetylserine sulfhydrylase A, incorporate only small quantities of O-acetyl-L-serine into 1,2,4-triazole-1-alanine in vivo. In vitro studies, using purified preparations of O-acetylserine sulfhydrylase A, revealed greater losses of triazolylase activity than sulfhydrylase activity in the enzymes from both cysK mutants. Resistance to 1,2,4-triazole apparently can arise from mutations leading to a preferential loss of triazolylase activity or from mutations which diminish both activities to the extent that high concentrations of O-acetyl-L-serine and sulfide accumulate behind the sulfhydrylase reaction.

Cysteine

Selective inhibition of virus multiplication by new acylated 1,2,4-triazole derivatives.

Six out of 99 new acylated 1,2,4-triazole derivatives specifically inhibited rubella virus replication in RK 13 cell cultures. These are the following: 3-methylthio-5-(2-chlorobenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-bromobenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-methylbenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-nitrobenzamido)-1H-1,2,4-triazole; 3-methylthio-5-(2-methylthiobenzamido)-1H-1,2,4-triazole and 3-ethylthio-5-(2-methylbenzamido)-1H-1,2,4-triazole. The compounds did not directly interfere with the infectivity of the rubella virus particles and the antiviral effect was demonstrable only within cells infected with rubella virus. The active compounds did not inhibit the replication of herpes simplex virus type 1, influenza virus and adenovirus in cell culture systems. Structure-activity relationships are discussed.

Adenoviruses, Human

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-na&#xef;ve 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

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