Synthesis of 3-carbamoyl-1,2,4-triazoles

3-Carbamoyl-1,2,4-triazoles were synthesized by the reaction of monothiooxamides with acid hydrazides Published inIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1487–1488, August, 2000.     

On the lead tetraacetate oxidation of 4-amino-1,2,4-triazoles, 1-amino- and 2-amino-1,2,3-triazoles

Lead tetraacetate oxidation of 4-amino-1,2,4-triazoles, 1-amino- and 2-amino-1,2,3-triazoles affords mainly fragmentation to nitriles or acetylenes, even in the presence of intramolecularly attached double bonds.

---

Über die Bleitetraacetatoxidation von 4-Amino-1,2,4-triazolen, 1-Amino- und 2-Amino-1,2,3-triazolen (Kurze Mitteilung)

Zusammenfassung Bei der Oxidation von 4-Amino-1,2,4-triazolen, 1-Amino- und 2-Amino-1,2,3-triazolen mit Bleitetraacetat entstanden hauptsächlich Nitrile bzw. Acetylene durch Fragmentierung — trotz der Gegenwart von intramolekularen Doppelbindungen.

     

Acyl and Sulfonyl Derivatives of 3,5-Diamino-1-R-1,2,4-triazoles

3-Acylamino-5-amino-1-R-1,2,4-triazoles are formed regioselectively on acylating 3,5-diamino-1-R-1,2,4-triazoles with an equimolar amount of anhydrides, carboxylic acid chlorides, and sulfonyl chlorides. With an excess of anhydride and carboxylic acid chloride 3,5-diacylamino-1-R-1,2,4-triazoles are formed. 3-Acylamino-5-amino-1-R-1,2,4-triazoles do not interact with sulfonyl chlorides. The higher reactivity of the 3-amino group towards acylating agents is determined by electronic and not steric factors. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1342–1350, September, 2005.     

Heterocyclic Synthesis Using Nitrilimines,Part 12: Synthesis and Bioactivity of 5-Carboxymethylthio-1,2,4-triazoles

The reaction of 4-amino-5-phenyl-3,5-thiaaza-4-pentenoic acid 3 with various nitrilimines 2 led to the formation of substituted carboxymethylthio derivatives of 1,2,4-triazoles (4a–l) rather than the amino derivatives 5 or imidazole derivatives 6. The spectral data of the synthesized compounds are in full agreement with its molecular structure.     

Thermal decomposition mechanisms of nitro-1,2,4-triazoles: A theoretical study

Possible decomposition mechanisms of C-nitro-and N-nitro-1,2,4-triazoles were simulated. We showed that in addition to the experimentally detected thermolysis products including N₂, N₂O, NO, CO₂, HCN, HNCO, 1,2,4-triazole, 3(5)-nitroso-1,2,4-triazole, and 1,2,4-triazolone, some other decompositon products (H₂O, CO, NO₂, cyanamide, cyanuric acid, and melamine) can be formed. Using the density functional approach (B3LYP/6-31G* approximation), we assessed the most favorable thermal decomposition pathways of nitrotriazoles and studied the relationships between the thermolysis pathways of these substances and their molecular and electronic structures. We found a correlation between the energy gap width (energy difference between the frontier molecular orbitals) and the stabilities of the C-nitro-1,2,4-triazole tautomers to thermal decomposition. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1338–1358, August, 2006.     

Molecular modeling of the mechanisms of thermolysis of nitramino-1,2,4-triazoles

Modeling of the probable mechanisms of the thermolysis of C-and N-nitramino-1,2,4-triazoles has been carried out by methods of mathematical chemistry. It was established that the formation is possible of a more diverse spectrum of products in their destruction than was previously recorded by different experimental methods. Subsequent assessment of the thermochemical preference for pathways of decomposition of the compounds was carried out by the density functional method in the B3LYP/6-31G* approach. It was determined that the thermal destruction of C-and N-nitramino-substituted polynitrogen heterocycles, capable of tautomeric conversion, was most probably through the thermochemically least stable nitramine form. Thermal decomposition of the considered tautomers is preferred at the NNO₂ fragment and not at the triazole ring. The direction of the structural stabilization of the investigated compounds has been clarified by comparison of the geometric, electronic, and thermochemical characteristics of C-NNO₂-and N-NNO₂-substituted 1,2,4-triazoles. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1467–1495, October, 2006.     

Heterocyclic synthesis using nitrile imines. 6. Synthesis of some new substituted 4,5-dihydro-1H-1,2,4-triazoles

A new series of substituted 1,2,4-triazoles was synthesized from the cycloaddition reaction of alkanal and cycloalkanal hydrazones containing electron-withdrawing groups (MeCO, PhCO, and MeOCO) with appropriate hydrazonoyl halides. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 392–398, March, 2007.     

Synthesis and Tuberculostatic Activity of 1,3-Thiazacycloalkyl[3,2-b]-1,2,4-triazoles

The 4-hydroxyalkyl-1,2,4-triazole-3-thiones cyclization allowed us to work out the effective method of 1,3-thiazacycloalkyl[3,2-b]-1,2,4-triazoles synthesis. Some of the compounds that were obtained were tested for their tuberculostatic activity.     

Synthesis of 3,5-Diaryl-4-benzylideneamino-1,2,4-triazoles and 4-Amino-3,5-diaryl-1,2,4-triazoles

A one-pot reaction leading to 3,5-diaryl-4-benzylideneamino-1,2,4-triazoles is described, the key step of which is the reaction of arenecarbohydrazonoyl chloride with benzylidenehydrazide. Compounds obtained in this way were hydrolyzed to 4-amino-3,5-diaryl-1,2,4-triazoles.     

Reactions of 3-nitro-1,2,4-triazole derivatives with alkylating agents. 5. Selective synthesis of 1,4-dialkyl-and 1,4,5-trialkyl-3-nitro-1,2,4-triazolium salts from 1-alkyl-and 4,5-dialkyl-3-nitro-1,2,4-triazoles and dialkyl sulfates

Interaction of N₍₁₎-alkyl-substituted 3-nitro-5-R-1,2,4-triazoles with dialkyl sulphates proceeds selectively and results in the respective salts of 1,4-dialkyl-, 1,4,5-trialkyl-3-nitro-1,2,4-triazoliums. The reaction of N₍₄₎-alkyl-substituted 3-nitro-5-R-1,2,4-triazoles yields the mixtures of the salts of 1,4-dialkyl-, 1,4,5-trialkyl-3-nitro-1,2,4-triazoliums and 1,4-dialkyl-, 1,3,4-trialkyl-1,2,4-triazol-5-ones with predominance of quaternary salts. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 927–934, June, 2007.     

Trimethylsilyl isothiocyanate (TMSNCS): an efficient reagent for the one-pot synthesis of mercapto-1,2,4-triazoles

A mild, convenient, and efficient one-pot synthesis of mercapto-1,2,4-triazoles is described. Various hydrazides efficiently reacted with trimethylsilyl isothiocyanate (TMSNCS) under basic condition to give mercapto-1,2,4-triazoles in high yields.     

Synthesis of new 1H-1,2,4-triazolylcoumarins and their antitumor and anti-HIV activities

A variety of 7-[(1,5-dialkyl-1H-1,2,4-triazolyl)methoxy(and methyl)]coumarins were synthesized from cycloaddition of 2-(2H-benzopyran-7-yloxy)acetonitrile and 2-(5-methoxy-4-methyl-2H-benzopyran-7-yloxy)acetonitrile, respectively, with various reactive cumulene intermediates via spontaneous rearrangements. The anticancer (breast, lung, CNS cancers) and antiviral (HIV-1, HIV-2) properties of some compounds were investigated in vitro. 5-Methoxy-4-methyl-7-[(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-2-yl)methyl]coumarin showed some inhibition of HIV-1. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 669–678, May, 2006.     

Brønsted acid-catalyzed simple and efficient synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles using 2,2,2-trichloroethyl imidates in PEG

A facile and highly efficient synthesis of 3,4,5-trisubstituted 1,2,4-triazoles and 3,5-disubstituted 1,2,4-oxadiazoles from 2,2,2-trichloroethyl imidates using PEG as a solvent and employing PTSA as the catalyst under mild conditions is described.     

Synthesis of novel fluorinated benzothiazol-2-yl-1,2,4-triazoles: Molecular docking,antifungal evaluation and in silico evaluation for SAR

Lead hybridization concept was used to design and synthesize twenty novel hybrid compounds by combining fungicidal leads viz. 6-flouro-1,3-benzothiazol-2-amine and 1,2,4-triazoles in a single molecule, with the aim of discovery of high potential novel fungicides. Antifungal evaluation of synthesized 6-flourobenzothiazol-2-yl-1,2,4-triazoles against various phytopathogenic fungi revealed synergistic effect of combination of leads with one another in all the test compounds. Some of the synthesized compounds showed excellent fungitoxicity comparable with the standard fungicides used. In silico toxicity of all the compounds was equivalent to the standard fungicides used. Docking studies and Lipinski filtration were performed in order to present the rationale of structure activity relation. Compounds 2, 8, 15 and 18 were screened to act as leads for further modification and use.     

ESR and polarography of nitroazoles. 7. Anion-radicals of isomers of N-methyl-C-nitro-1,2,4-triazole

The anion-radicals of N-methyl-substituted 3-nitro-1,2,4-triazole have been studied by polarography, ESR, and quantum-chemical methods. The difference in electrochemical behavior of the N-methyl isomers of 3-nitro-1,2,4-triazole has been analyzed. The spin distributions in their anion-radicals have been investigated by quantum-chemical methods. The theoretical data obtained are in poor agreement with experiment. By varying the structural characteristics of the anion-radicals internal geometric parameters have been separated out which prove to have the greatest effect on spin distributions. Geometric structures were established for the investigated isomers by minimizing the functional describing the disagreement of the theoretical and experimental spin distributions on the magnetic nuclei. The calculated hyperfine structure constants for the magnetically active nuclei for the structures obtained were in good agreement with experiment. The influence of solvation effects on the electronic structure parameters of the nitrotriazole anion-radicals has been investigated. Hydrated complexes containing four molecules of water proved to be the most stable. Structural deformation of the solvated anion-radicals occurs in the same direction as on minimizing the functional.For part 6 see [1].Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk 664033, Russia; e-mail: vti@irioch.irk.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 193–202, February, 2000.     

Quantum chemical calculations of the isomer shift in iron(II) complexes of 1,2,4-triazoles with a 1 A 1 ⇔ 5 T 2 spin transition

DFT calculations have been performed to determine the isomer shift for a series of iron(II) clusters with nitrogen-containing ligands which serve as models of coordination units in Fe(II) complexes with 1,2,4-triazoles possessing a ¹ A ₁ ? ⁵ T ₂ spin transition. Good agreement has been found between the theoretical and experimental values of the isomer shift for both low-and high-spin phases. Our calculations confirmed the hypothesis about relationship between the experimentally observed differences in the isomer shift for the low-spin phases of the complexes and variations of the Fe-N mean bond length.     

Synthesis and Antibacterial Activity of Some New Derivatives of Thiosemicarbazide and 1,2,4-Triazole

Abstract

In a reaction of hydrazides of cyclohexylacetic acid 1 and phenylacetic acid 2 with isothiocyanates, respective thiosemicarbazide derivatives 3–18 were obtained. Further cyclization with 2% NaOH led to the formation of 5-(cyclohexylmethyl/benzyl)-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones 19–34. Structures of all new products were confirmed by analytical and spectroscopic methods. All compounds were screened for their in vitro activity against some species of bacteria and fungi.

[Supplementary materials are available for this article. Go to the publisher's online edition ofPhosphorus, Sulfer, and Silicon and the Related Elements for the following free supplemental files: Additional figures and tables.]     

Synthesis of Biologically Relevant 1,2,3- and 1,3,4-Triazoles: From Classical Pathway to Green Chemistry

Green Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems.     

Synthesis of 1-amino-1,2,4-triazolium 4-nitroimides and their reactions with electrophiles

A procedure was developed for the preparation of 1-amino-1,2,4-triazolium 4 nitroimides by amination of triethylammonium salts of 4-nitramino-1,2,4-triazoles with O-picrylhydroxylamine. The resulting nitroimides reacted with electrophilic reagents (acyl chlorides, aldehydes, phenyl isocyanate, NO₂BF₄, etc.) at the amino group.     

New 1,2,3-Triazole-Coumarin-Glycoside Hybrids and Their 1,2,4-Triazolyl Thioglycoside Analogs Targeting Mitochondria Apoptotic Pathway: Synthesis,Anticancer Activity and Docking Simulation

Toxicity and resistance to newly synthesized anticancer drugs represent a challenging phenomenon of intensified concern arising from variation in drug targets and consequently the prevalence of the latter concern requires further research. The current research reports the design, synthesis, and anticancer activity of new 1,2,3-triazole-coumarin-glycosyl hybrids and their 1,2,4-triazole thioglycosides as well as acyclic analogs. The cytotoxic activity of the synthesized products was studied against a panel of human cancer cell lines. Compounds 8, 10, 16 and 21 resulted in higher activities against different human cancer cells. The impact of the hybrid derivative 10 upon different apoptotic protein markers, including cytochrome c, Bcl-2, Bax, and caspase-7 along with its effect on the cell cycle was investigated. It revealed a mitochondria-apoptotic effect on MCF-7 cells and had the ability to upregulate pro-apoptotic Bax protein and downregulate anti-apoptotic Bcl-2 protein and thus implies the apoptotic fate of the cells. Furthermore, the inhibitory activities against EGFR, VEGFR-2 and CDK-2/cyclin A2 kinases for 8, 10 and 21 were studied to detect the mechanism of their high potency. The coumarin-triazole-glycosyl hybrids 8 and 10 illustrated excellent broad inhibitory activity (IC₅₀= 0.22 ± 0.01, 0.93 ± 0.42 and 0.24 ± 0.20 μM, respectively, for compound 8), (IC₅₀ = 0.12 ± 0.50, 0.79 ± 0.14 and 0.15± 0. 60 μM, respectively, for compound 10), in comparison with the reference drugs, erlotinib, sorafenib and roscovitine (IC₅₀ = 0.18 ± 0.05, 1.58 ± 0.11 and 0.46 ± 0.30 μM, respectively). In addition, the docking study was simulated to afford better rationalization and put insight into the binding affinity between the promising derivatives and their targeted enzymes and that might be used as an optimum lead for further modification in the anticancer field.