Triazoles
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Triazoles are used as antifungal agents, they mostly inhibit two enzymes: 14α-demethylase and aromatase. These enzymes are utilised also in other species and therefore the affection in non-target species in the environment is expected as well. Besides, triazoles are often being applied in a mixture and they can also interact with other substances present. This study clarifies how three selected representative triazoles (tebuconazole, penconazole and cyproconazole) interact with each other (group effect) and in mixtures (cocktail effect) with copper, essential/toxic for all organisms. Within the experiments on electrospray and collision-induced dissociations (both ESI-MS), it has been found that the fragments correspond to typical triazole metabolites. For their formation, the presence of copper ions is crucial. The inhibitory effect of Cu cocktails on aromatase enzymatic activity has been studied. The presence of Cu ions together with triazole(s) significantly increases the inhibitory effect on aromatase activity. The highest inhibitory effect (more than 60%) on aromatase activity is produced by cocktails containing penconazole and Cu ions, namely by penconazole/Cu and penconazole/tebuconazole/Cu. The reactivity of triazoles in groups is not significantly affected by the interactions among them. Additionally, the role of triazoles in copper Fenton reaction regulation has been observed and described. These changes may be attributed to the formation and stabilization of the complexes with the central Cu ion, with usually one, two or three triazolic ligands, depending on the mixture. The study demonstrates that the interaction of triazoles and Cu ions is a complex process; their impact on metabolism seems to be rather extensive and must be evaluated in the context of biochemical reactions.
- MeSH
- antifungální látky MeSH
- aromatasa * MeSH
- měď * MeSH
- oxidace-redukce MeSH
- triazoly MeSH
- Publikační typ
- časopisecké články MeSH
Glycosyl 1,2,3-triazoles with alpha-D-gluco, beta-D-gluco, alpha-D-galacto, beta-D-galacto and beta-2-acetamido-2-deoxygluco (GlcNAc) stereochemistry were prepared by reaction of the corresponding azides with vinyl acetate under microwave irradiation. The deprotected glucosyl and galactosyl triazoles did not display inhibitory activity against the tested glycosidases at 1 mM. Of the four fungal glycosidases evaluated, GlcNAc-triazole was found to be hydrolyzed by Talaromyces flavus CCF 2686 beta-N-acetylhexosaminidase. Beta-GlcNAc-triazole was furthermore established to act as a strong ligand of rat and human natural killer cell activating receptors.
- MeSH
- hydrolýza MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- triazoly chemická syntéza farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.
- MeSH
- alkoholoxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- bakteriální proteiny antagonisté a inhibitory metabolismus MeSH
- dinitrobenzeny chemická syntéza chemie farmakologie MeSH
- fluorované uhlovodíky chemická syntéza chemie farmakologie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků enzymologie MeSH
- triazoly chemická syntéza chemie farmakologie MeSH
- vyvíjení léků * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Copper-free click reactions between a dibenzoazocine derivative and azides derived from 5-methyluridine were investigated. The non-catalyzed reaction yielded both regioisomers in an approximately equivalent ratio. The NMR spectra of each regioisomer revealed conformational isomery. The ratio of isomers was dependent on the type of regioisomer and the type of solvent. The synthesis of various analogs, a detailed NMR study and computational modeling provided evidence that the isomery was dependent on the interaction of the azocine and pyrimidine parts.
In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.
- MeSH
- benzaldehydy chemie MeSH
- buněčný cyklus účinky léků MeSH
- cykloadiční reakce MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemie farmakologie MeSH
- triazoly chemie MeSH
- triterpeny chemie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Článek představuje výsledky studia antimikrobiálních a antimykotických vlastností derivátů 1,2,4-triazolu syntetizovanými na Katedře fyzikální a koloidní chemie Záporožské státní lékařské univerzity. Předchozí studie stanovily antimikrobiální a antimykotickou aktivitu derivátů 1,2,4-triazolu. Proto bylo účelné zkoumat mezi syntetizovanými sloučeninami vysoce účinné látky s antimikrobiálními a antimykotickými vlastnostmi. V první fázi našeho výzkumu byla provedena predikce akutní toxicity. Antimikrobiální a antimykotické vlastnosti byly provedeny metodou sériového ředění na kapalné živné půdě. Na tyto typy aktivit bylo zkoumáno 47 sloučenin různých tříd. Podle našeho výzkumu vykazovaly deriváty 3-amino-1,2,4-triazolu lepší účinnost než 3-thio-1,2,4-triazoly na Staphylococcus aureus a Candida albicans. Největší antimikrobiální a antimykotickou aktivitu vykazoval 5-(1Н-tetrazol-1-іl)methyl-4Н-1,2,4-triazol- 3-yl-1-(5-nitrofuran-2-yl)methanimin (11.6). Hlubší výzkum sloučeniny 11.6 byl proveden difuzí v agaru (jamková metoda). Studie ukázaly, že molekula 11.6 vykazovala antimikrobiální a antimykotický účinek na studované testovací kmeny v koncentraci 2 μg/ml. Proto může být tato sloučenina po zjištění její farmakologické bezpečnosti a toxicity vyvinuta jako užitečná léčivá látka.
This article presents the results of the study of the antimicrobial and antifungal properties among 1,2,4-triazole derivatives synthesized at the Department of Physical and Colloidal Chemistry of the Zaporizhzhia State Medical University. Previous studies have established the antimicrobial and antifungal activity of 1,2,4-triazole derivatives. Therefore, it was reasonable to investigate highly effective substances with antimicrobial and antifungal properties among synthesized compounds. In the first stage of our research, acute toxicity prediction was performed. The antimicrobial and antifungal properties were carried out by the method of “serial dilutions” on a liquid nutrient. Forty-seven compounds of the different classes were studied for these types of activities. According to our research, derivatives of 3-amino-1,2,4-triazole showed better performance than 3-thio-1,2.4-triazoles for Staphylococcus aureus and Candida albicans. 5-(1Н-tetrazole-1-іl)methyl-4Н- -1,2,4-triazole-3-yl-1-(5-nitrofuran-2-yl)methanimin (11.6) was showed the greatest antimicrobial and antifungal activity. Deeper research for compound 11.6 was done by diffusion in agar (method of “wells”). Studies have shown that molecule 11.6 showed antimicrobial and antifungal action to the studied test strains at a concentration of 2 μg/ml. Hence, this compound can be developed as a helpful therapeutic agent after establishing its safety pharmacology and toxicity.
- MeSH
- agar MeSH
- antibakteriální látky farmakologie MeSH
- antifungální látky farmakologie MeSH
- antiinfekční látky farmakologie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- nitrofurany chemie farmakologie MeSH
- tetrazoly chemie farmakologie MeSH
- triazoly * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
