Triazole Compounds Research Articles

Immobilization and Release Studies of Triazole Derivatives from Grafted Copolymer Based on Gellan-Carrying Betaine Units.

New polymer-bioactive compound systems were obtained by immobilization of triazole derivatives onto grafted copolymers and grafted copolymers carrying betaine units based on gellan and N-vinylimidazole. For preparation of bioactive compound, two new types of heterocyclic thio-derivatives with different substituents were combined in a single molecule to increase the selectivity of the biological action. The 5-aryl-amino-1,3,4 thiadiazole and 5-mercapto-1,2,4-triazole derivatives, each containing 2-mercapto-benzoxazole nucleus, were prepared by an intramolecular cyclization of thiosemicarbazides-1,4 disubstituted in acidic and basic medium. The structures of the new bioactive compounds were confirmed by elemental and spectral analysis (FT-IR and 1H-NMR). The antimicrobial activity of 1,3,4 thiadiazoles and 1,2,4 triazoles was tested on gram-positive and gram-negative bacteria. The triazole compound was chosen to be immobilized onto polymeric particles by adsorption. The Langmuir, Freundlich, and Dubinin–Radushkevich adsorption isotherm were used to describe the adsorption equilibrium. Also, the pseudo-first and pseudo-second models were used to elucidate the adsorption mechanism of triazole onto grafted copolymer based on N-vinylimidazole and gellan (PG copolymer) and grafted copolymers carrying betaine units (PGB1 copolymer). In vitro release studies have shown that the release mechanism of triazole from PG and PGB1 copolymers is characteristic of an anomalous transport mechanism.

On the protonation of a polysubstituted 1,2,4-triazole: A structural study of a hexabromotellurate salt

Previous findings in the chemistry of 5-amino-1,2,4-triazol-3-thioles show the possibility of protonation of such systems on the nitrogen atom in position 1 of the triazole ring. To expand the molecular design synthetic strategies for triazole systems, it was suggested that the weakening of the basicity of the guanidine fragment via the introduction of a phenyl ring from one side and addition of a flexible 3-(carboxymethyl)sulfanyl moiety in position 3 of the cycle can lead to the formation of a triazole compound that would attach a proton on the nitrogen atom in the second position of the ring. Synthesis of the model 3-[(carboxymethyl)sulfanyl]-4-phenyl-5-phenylamino-4H-1,2,4-triazole via the selective S-alkylation of known 4-phenyl-5-phenylamino-1,2,4-triazole-3-thione has been performed. The synthesized triazole amino acid was converted into a corresponding hexabromotellurate salt which has been further explored and characterized via DFT, NMR and XRD methods.

WITHDRAWN: Synthesis, docking study, and in-vitro anti-cancer evaluation of new triazole derivatives of flufenamic acid

The new triazole compounds derived from the parent flufenamic acid (FLU) were synthesized by a conventional method. The molecular-docking study of the synthesized compounds(s) against EGFR kinase revealed that such compounds occupied the critical site of EGFR kinase pocket with good positioning. Compound 8 exhibited cytotoxic activity against MCF-7 breast cancer cells (GI 50 0.78 µM), and not against A549 lung cancer cells or normal cells, and this toxic effect was due to induction of the intrinsic apoptotic pathway. Moreover compound 8 showed an inhibitory effect against EGFR kinase. Novel compounds were synthesized and confirmed by spectroscopic analysis, including AT-IR, 1 HNMR S and CHNS. Compound 8 apoptosis induction was evident by fragmented nuclei after DAPI staining and smeared DNA by agarose gel electrophoresis. Additionally, treating MCF-7 cells with compound 8 resulted in an increment in the level of caspase 9 mRNA level, and its activation. Moreover, compound 8 -treated MCF-7 cells showed enhanced cytochrome-c release from the mitochondria to cytosol indicating an induction for the intrinsic apoptotic pathway. Finally, compound 8 showed comparable EGFR kinase inhibitory activity (3.4 µM) to erlotinib (1.22 µM), which was matched by the molecular docking studies that showed that the target compounds may be considered as potential inhibitors of EGFR kinase.

A review on ‘triazoles’: their chemistry, synthesis and pharmacological potentials

Heterocyclic compounds are cyclic compounds as an atom of ring members with at least two different elements. In the five-membered aromatic azole chain, triazole compounds containing two carbon and three nitrogen atoms are readily capable of binding in the biological system with a variety of enzymes and receptors and thus show versatile biological activities. In the 1960s, the Janseen Group discovered the first compound of this class. Triazole commonly called pyrrodiazole is nitrogenous heterocyclic moiety and has molecular formula C2H3N3. Triazole nucleus is present as a central structural component in a number of drug classes such as antibacterial, antifungal, anticancer, antioxidant, antiviral, anti-inflammatory, analgesic, antiepileptic, antihypertensive, antidepressant, antidiabetic, antianxiety and antitubercular. The commercially available triazole-containing drugs are fluconazole, voriconazole (antifungal), trazodone, nefazodone (antidepressant), trapidil (antihypertensive), estazolam (sedative-hypnotic), rufinamide (antiepileptic) and so on. This paper aims to analyze the synthesis and pharmacological activities recorded in the current literature for triazole derivatives. Along with the therapeutic importance of triazole derivatives as confirmed in the literature, it was decided to synthesize and study their antimicrobial, antioxidant and antiviral potential of substituted 1,2,4-triazole analogues. The literature-based design of triazole moiety is present in Fig 1.

XRD, NMR, FT-IR and DFT structural characterization of a novel organic-inorganic hybrid perovskite-type hexabromotellurate material

The synthesis of a new hexabromotellurate of triazole ring-containing amino acid is described. XRD, NMR and DFT analysis of the structure of protonated [(5-amino-4-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]acetic acid testifies the protonation of the first nitrogen atom of the triazole ring. Hirshfeld surface analysis identifies numerous intermolecular interactions in the newly synthesized organic-inorganic hybrid hexabromotellurate. The DFT based comprehensive analysis of the structures of possible conformers also testifies the higher thermodynamic stability of the 1-protonated triazole cation, whereas the starting [(5-amino-4-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]acetic acid exists in solution in neutral form with the intermolecular hydrogen bond between the carboxylic acid OH group and the second nitrogen of the triazole ring. The experimentally observed NMR upfield shift of the signal of the exocyclic amino group was studied via GIAO computations and was explained through the analysis of the HOMOs of the neutral and protonated forms of the triazole compound.

Genetic and Phenotypic Characterization of in-Host Developed Azole-Resistant Aspergillus flavus Isolates.

Aspergillus flavus is a pathogenic fungal species that can cause pulmonary aspergillosis, and triazole compounds are used for the treatment of these infections. Prolonged exposure to azoles may select for compensatory mutations in the A. flavus genome, resulting in azole resistance. Here, we characterize a series of 11 isogenic A. flavus strains isolated from a patient with pulmonary aspergillosis. Over a period of three months, the initially azole-susceptible strain developed itraconazole and voriconazole resistance. Short tandem repeat analysis and whole-genome sequencing revealed the high genetic relatedness of all isolates, indicating an infection with one single isolate. In contrast, the isolates were macroscopically highly diverse, suggesting an adaptation to the environment due to (epi)genetic changes. The whole-genome sequencing of susceptible and azole-resistant strains showed a number of mutations that might be associated with azole resistance. The majority of resistant strains contain a Y119F mutation in the Cyp51A gene, which corresponds to the Y121F mutation found in A. fumigatus. One azole-resistant strain demonstrated a divergent set of mutations, including a V99A mutation in a major facilitator superfamily (MSF) multidrug transporter (AFLA 083950).

Antioxidant and anti-sickling activity of glucal-based triazoles compounds – An in vitro and in silico study

The sickle cell disease (SCD) has a genetic cause, characterized by a replacement of glutamic acid to valine in the β-chain of hemoglobin. The disease has no effective treatment so far, and patients suffer a range from acute to chronic complications that include chronic hemolytic anemia, vaso-occlusive ischemia, pain, acute thoracic syndrome, cerebrovascular accident, nephropathy, osteonecrosis and reduced lifetime. The oxidation in certain regions of the hemoglobin favors the reactive oxygen species (ROS) formation, which is the cause of many clinical manifestations. Antioxidants have been studied to reduce the hemoglobin ROS levels, and in this sense, we have searched for new antioxidants glucal-based triazoles compounds with anti-sickling activity. Thirty analogues were synthetized and tested in in vitro antioxidant assays. Two of them were selected based in their effects and concentration–response activity and conducted to in cell assays. Both molecules did not cause any hemolysis and could reduce the red blood cell damage caused by hydrogen peroxide, in a model of oxidative stress induction that mimics the SCD. Moreover, one molecule (termed 11m), besides reducing the hemolysis, was able to prevent the cell damage caused by the hydrogen peroxide. Later on, by in silico pharmacokinetics analysis, we could see that 11m has appropriated proprieties for druggability and the probable mechanism of action is the binding to Peroxiredoxin-5, an antioxidant enzyme that reduces the hydrogen peroxide levels, verified after molecular docking assays. Thus, starting from 30 glucal-based triazoles molecules in a structure–activity relationship, we could select one with antioxidant proprieties that could act on RBC to reduce the oxidative stress, being useful for the treatment of SCD.

IN SILICO CHARACTERIZATION, MOLECULAR DOCKING, AND IN VITRO EVALUATION OF TRIAZOLE DERIVATIVES AS POTENTIAL ANTICANCER AGENTS

Objective: The objective of the study was to perform in silico molecular docking and in vitro anticancer studies of proposed 1,2,4-triazole derivatives for the determination of their anticancer activity.
 Methods: A series of 10 triazole compounds with different substituents were drawn in ACD Lab ChemSketch software. Molecular and biological properties were identified using Molinspiration software. The compounds that obeyed Lipinski rule of five are subjected for pharmacokinetic parameters prediction and docking analysis. SwissDock ADME software is used for the prediction of absorption, distribution, metabolism, and elimination. Then, the compounds are docked with target enzymes in Chimera software 1.14 version. The molecular docking studies revealed favorable molecular interactions and binding energies. The compounds that showed good docking results were synthesized through wet lab synthesis and further preceded for in vitro anticancer studies.
 Results: Three compounds are selected for wet lab synthesis due to their good docking results compared to other compounds. The synthesized compounds are subjected to different in vitro anticancer studies and found to be having potential anticancer activity.
 Conclusion: The pharmacokinetic and docking studies conclude that the triazole compounds have potential as anticancer agents. The in vitro anticancer studies revealed that the triazole derivatives are having high potency of anticancer activity against pancreatic cell lines.

Synthesis, Cyrstal Structure and Fungicidal Activity of New Triazole Compounds Containing Trifluoromethylphenyl Moiety

Synthesis, Cyrstal Structure and Fungicidal Activity of New Triazole Compounds Containing Trifluoromethylphenyl Moiety

Synthesis and Insecticidal Activity of 3-Ethyl Sulfone Pyridine Substituted Aryl Triazole Compounds

Synthesis and Insecticidal Activity of 3-Ethyl Sulfone Pyridine Substituted Aryl Triazole Compounds

Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity

A group of triazole compounds was selected to investigate the confidence that may be associated with read-across of a complex data gap: repeated dose toxicity. The read-across was evaluated using Assessment Elements (AEs) from the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF), alongside appraisal of associated uncertainties. Following an initial read-across based on chemical structure and properties, uncertainties were reduced by the integration of data streams such as those from New Approach Methodologies (NAM) and other existing data. In addition, addressing the findings of the ECHA RAAF framework, complemented with specific questions concerning uncertainties, increased the confidence that can be placed in read-across. Although a data rich group of compounds with a strong mechanistic basis was analysed, it was clearly demonstrated that NAM data available from publicly available resources could be applied to support read-across. It is acknowledged that most read-across studies will not be so data rich or mechanistically robust, therefore some targeted experimentation may be required to fill the data gaps. In this sense, NAMs should constitute new experimental tests performed with the specific goal of reducing the uncertainties and demonstrating the read-across hypothesis.

Synthesis and Characterization of Some Heterocyclic Compounds and Evaluation of Antibacterial Activity

In this study, heterocyclic compounds with two nitrogen atoms are prepared by reaction of 2-aminobenzimidazole with formic acid to get amide derivatives (A), reacts with phenylhydrazine to get phenyl hydrazone derivatives (B), reacts with ethyl chloroacetate to obtain ethyl acetate derivatives (C). The derivative (D) obtains on heating in a basic medium. The (B) reacts with 2-chloroacetyl chloride to give derivatives (E). A number of Schiff bases are prepared (F, I) from reacting 2-aminobenzimidazole with benzaldehyde derivatives. The(F) reacts with propargyl bromide to give propargyl bromide derivatives (G). The cyclization with 4-nitrophenyl azide leads to obtain triazole compound (H). The compound (I) reacts with ethyl chloroacetate to give ethyl acetate derivatives (J), reacts with hydrazine to give N-amide hydrazine derivatives (K). The cyclization give rises to 1,3,4-oxadiazole derivatives (L). The compound (I) reacts with sodium azide to obtain tetrazole derivatives (M). Synthesizing of Triazine, Oxadiazole, Triazole, Tetrazole via cyclization of the Schiff base derivatives with ethyl chloroacetate and chloro acetyl chloride, benzoic acid, 4-nitrophenyl azide, sodium azide and phenyl azide are possible respectively. The FT-IR, 13C-NMR and 1H-NMR spectral data give good evidence for the formation of the compounds. Some prepared compounds exhibit antibacterial properties.

Changes in Cytochrome b Gene Expression in Cochliobolus sativus Induced by Triadimefon, a Triazole Fungicide

Introduction: Spot blotch, caused by Cochliobolus sativus, is most effectively managed using fungicide applications, including triadimefon (TDM) a triazole compound. C. sativus posses a great concern as it might develop resistance against fungicides like TDM due to its high genetic variability, short life cycle, and abundant inoculum production. Therefore, to better understand the mechanisms of TDM resistance initiated by C. sativus, changes in cytochrome b (cytb) gene in virulent and avirulent pathotypes were evaluated at early time points of TDM treatments. Materials and Methods: C. sativus sensitivity to TDM was determined by measuring the radial growth of each pathotype on PDA plates. Additionally, RNA was isolated from mycelia of each pathotype at 24, 48, 72 and 96 hours post fungicide treatments and used for cDNA synthesis. Cytb was verified using quantitative reverse transcriptase PCR (qRT-PCR). Results: Data showed that the maximum mycelial growth inhibition by 50% (EC50) for both pathotypes was recorded 48h at 0.25 µg/ml TDM treatment. The qRT-PCR revealed that cytb expression increased in both virulent and avirulent pathotypes at 24h post TDM treatments in comparison with non-treated controls. The most outstanding differences in cytb expression were7.69 and 2.88-fold in the virulent and avirulent pathotypes, respectively, 48h of 0.25 µg/ml TDM treatment. Conclusions: According to findings, it is possible to propose that cytb gene might play a role in signaling events during C. sativus exposure to commercial triazole fungicide.

Chamber Protection of Copper from Atmospheric Corrosion by Compounds of the Triazole Class

Using a set of physicochemical (ellipsometry and contact angle measurements), electrochemical (electrochemical impedance spectroscopy and polarization measurements), and corrosion (periodic moisture condensation and salt fog tests) methods, the properties of adsorption films formed on copper by the chamber method from vapors of benzotriazol (BTA), 1H-1,2,4-triazole, tolyltriazole (TTA), 5-chloro-1,2,3-benzotriazole (CBTA), 3-amino-1H-1,2,4-triazole, and 4-amino-1H-1,2,4-triazole at a temperature of 100°C are studied. It is shown that 1-h chamber treatment of copper with vapors of these compounds leads to the formation of nanoscale hydrophobic adsorption films on it, which inhibits the thermal growth of oxides, but stabilizes the passive state of the metal and increases its corrosion resistance. Among these different triazole compounds tested as chamber corrosion inhibitors, BTA and its substituted derivatives are distinguished. After a 1-h chamber treatment of copper, the protective aftereffect of the adsorption films of triazole derivatives grows symbatically with their saturated vapor pressure at the chamber treatment temperature, i.e., in the following increasing order: CBTA < TTA < BTA. This may indicate that the equilibrium adsorption films do not have time to form at 100°С on the metal within this time period. After a prolonged (24 h or more) chamber treatment of copper with vapors of substituted benzotriazoles, equilibrium adsorption films of inhibitors are formed on it. In this case, the influence of the chamber inhibitor properties on their protective aftereffect alternates. Under such conditions, the least volatile and most hydrophobic substituted benzotriazole, i.e., CBTA, provide the best metal protection.

Appraisal of water matrix on the removal of fungicide residues by heterogeneous photocatalytic treatment using UV-LED lamp as light source.

In this study, the photocatalytic degradation of four fungicides, myclobutanil, penconazole and difenoconazole (triazole compounds) and boscalid (carboxamide), has been examined in different aqueous matrices (tap water, irrigation water and two WWPT effluents). Experiments were conducted at laboratory scale with different reagents-zinc oxide (ZnO), titanium dioxide (TiO2), sodium persulphate (Na2S2O8) and the combined systems ZnO/Na2S2O8 and TiO2/Na2S2O8-in water exposed to UV-LED irradiation. Previously, the effect of catalyst and oxidant loading on the disappearance kinetics of the different fungicides was assessed to know maximum degradation efficiency. The influence of water matrices and pesticide loading in removal effectiveness has been evaluated. It was observed a greater efficiency in processes conducted using the tandems ZnO/Na2S2O8 and TiO2/Na2S2O8 in irrigation and tap waters. Results showed that UV-LED are a suitable alternative for tackling the removal of organic pollutants in water.

Design, synthesis and effect of triazole derivatives against some toxic activities of Bothrops jararaca venom

According to the World Health Organization, snakebite envenoming is a neglected disease that affects around 5.4 million people worldwide each year. In Brazil, in 2019 there were 29,000 cases of accidents, with 104 deaths. The genus Bothrops was responsible for 90% of reported envenomations, mainly the species B. jararaca. The current therapy is performed with an intravenous injection of antivenom, be it monovalent or polyvalent. However, this treatment has high manufacturing costs, may induce side effects, and it does not effectively neutralize tissue necrosis. The latter issue may lead to deformity or amputation of the affected limb. Therefore, new treatments are needed to aid or improve the efficacy of antivenoms. In this study, nine triazole compounds (AM11–AM19) were chemically synthesized, characterized using infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy analyses, and tested against some in vitro (hemolysis, coagulation, and proteolysis) and in vivo (hemorrhaging, lethal, and edema) activities of B. jararaca venom. Each compound was incubated with B. jararaca venom (incubation protocol) or injected after the venom (treatment protocol), and then, biological assays were performed. As a result, all the compounds inhibited the toxic activities of B. jararaca venom with different potencies in the incubation protocol, while the compound AM13 inhibited hemorrhaging in the treatment protocol. In addition, the compounds were devoid of toxicity, as shown through admetSAR analysis or in vitro cytotoxicity test. Thus, these compounds may be an important tool for the development of antivenom molecules to improve serum therapy for recovering patients envenomed by B. jararaca venom.

1,4-Disubstituted-1,2,3-Triazole Compounds Induce Ultrastructural Alterations in Leishmania amazonensis Promastigote: An in Vitro Antileishmanial and in Silico Pharmacokinetic Study.

The current standard treatment for leishmaniasis has remained the same for over 100 years, despite inducing several adverse effects and increasing cases of resistance. In this study we evaluated the in vitro antileishmanial activity of 1,4-disubstituted-1,2,3 triazole compounds and carried out in silico predictive study of their pharmacokinetic and toxicity properties. Ten compounds were analyzed, with compound 6 notably presenting IC50: 14.64 ± 4.392 µM against promastigotes, IC50: 17.78 ± 3.257 µM against intracellular amastigotes, CC50: 547.88 ± 3.256 µM against BALB/c peritoneal macrophages, and 30.81-fold selectivity for the parasite over the cells. It also resulted in a remarkable decrease in all the parameters of in vitro infection. Ultrastructural analysis revealed lipid corpuscles, a nucleus with discontinuity of the nuclear membrane, a change in nuclear chromatin, and kinetoplast swelling with breakdown of the mitochondrial cristae and electron-density loss induced by 1,4-disubstituted-1,2,3-triazole treatment. In addition, compound 6 enhanced 2.3-fold the nitrite levels in the Leishmania-stimulated macrophages. In silico pharmacokinetic prediction of compound 6 revealed that it is not recommended for topical formulation cutaneous leishmaniasis treatment, however the other properties exhibited results that were similar or even better than miltefosine, making it a good candidate for further in vivo studies against Leishmania parasites.

Cu2O/reduced graphene oxide/TiO2nanomaterial: An effective photocatalyst for azide‐alkyne cycloaddition with benzyl halides or epoxide derivatives under visible light irradiation

Cu2O/reduced graphene oxide/TiO2(Cu2O/rGO/TiO2) photocatalyst was synthesized under ultrasonic irradiation. The nanomaterial was identified by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X‐ray diffraction (XRD), Raman spectroscopy, X‐ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT‐IR) spectroscopy, UV–vis absorption, and inductively coupled plasma optical emission spectroscopy (ICP‐OES). The Cu2O/rGO/TiO2photocatalyst was utilized in “click” reaction for the preparation of 1,4‐disubstituted 1,2,3‐triazoles via one pot multicomponent reaction of benzyl halide or epoxide derivatives with alkynes in presence of NaN3and triethylamine under visible light irradiation. The “click” reaction was performed under mild conditions affording good to excellent yields of the triazole compounds using low catalyst loading in short reaction times. The nanocomposite was recovered and recycled for five successive runs without a major diminution in its catalytic performance.

Synthesis of Novel 1,2,3-Triazole Derivatives of Isocoumarins and 3,4-Dihydroisocoumarin with Potential Antiplasmodial Activity In Vitro.

Malaria greatly affects the world health, having caused more than 228 million cases only in 2018. The emergence of drug resistance is one of the main problems in its treatment, demonstrating the need for the development of new antimalarial drugs. Synthesis and in vitro antiplasmodial evaluation of triazole compounds derived from isocoumarins and a 3,4-dihydroisocoumarin. The compounds were synthesized in 4 to 6-step reactions with the formation of the triazole ring via the Copper(I)-catalyzed 1,3-dipolar cycloaddition between isocoumarin or 3,4- dihydroisocoumarin azides and terminal alkynes. This key reaction provided compounds with an unprecedented connection of isocoumarin or 3,4-dihydroisocoumarin and the 1,2,3-triazole ring. The products were tested for their antiplasmodial activity against a Plasmodium falciparum chloroquine resistant and sensitive strains (W2 and 3D7, respectively). Thirty-one substances were efficiently obtained by the proposed routes with an overall yield of 25-53%. The active substances in the antiplasmodial test displayed IC50 values ranging from 0.68-2.89 μM and 0.85-2.07 μM against W2 and 3D7 strains, respectively. This study demonstrated the great potential of isocoumarin or 3,4-dihydroisocoumarin derivatives because practically all the tested substances were active against Plasmodium falciparum.

The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity.

Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.