Synthesis and properties of some 3-(5-(4-methoxyphenyl)pyrazol-3-yl)-6-R-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Authors

DOI:

https://doi.org/10.14739/2409-2932.2022.2.259227

Keywords:

1,2,4-triazole, pyrazole, physicochemical properties, molecular docking

Abstract

Pyrazole and 1,2,4-triazole derivatives play an important strategic role in modern medicine and pharmacy. This fact is due to the significant possibilities of chemical modification and significant pharmacological potential among the derivatives of these heterocycles. The introduction of 1,2,4-triazole and pyrazole fragments into the structure of new substances allows to influence the formation of a certain type of activity. The structural combination of these heterocycles in one molecule increases the likelihood of interaction with various biological targets. At the same time, the creation of condensed systems involving 1,2,4-triazole is undoubtedly scientifically attractive and promising.

The aim of the research was to study the conditions for obtaining 3-(5-(4-methoxyphenyl)pyrazol-3-yl)-6-R-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and studying the properties of these compounds.

Materials and methods. The first stage of the synthetic part of the work involved the use of diethyl oxalate and 1-(4-methoxyphenyl)ethan-1-one with the participation of sodium hydride in toluene. The obtained ethyl 4-hydroxy-4-(4-methoxyphenyl)-2-oxobut-3-ethanoate in the next step was used in the process of conversion into ethyl 5-(4-methoxyphenyl)pyrazole-3-carboxylate with the participation of hydrazine hydrate. Further modification of the molecule was the stepwise formation of the structure of 4-amino-5-(5-(4-methoxyphenyl)pyrazol-3-yl)-1,2,4-triazole-3-thiol. The next stage of the work involved the interaction with carboxylic acids in the environment of phosphorus oxychloride. To determine the composition and identify the structure of the isolated substances, 1H NMR and infrared spectra were recorded, as well as qualitative and quantitative indicators of the elemental composition of the synthesized structures were obtained. The individual nature of the presence of substances and the degree of their purity were determined using high performance liquid chromatography.

Results. Synthesis of 3-(5-(4-methoxyphenyl)pyrazol-3-yl)-6-R-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles was performed and optimal conditions were determined the process of obtaining these substances. The structure of the products of chemical transformation was confirmed and the results of the study of physical properties were recorded. The results of docking studies allowed to confirm the prospects of the chosen direction of synthetic transformations, which ultimately allowed to determine the biological potential of the obtained compounds. The model enzyme was 14-α-demethylase lanosterol (code 3LD6), information on which was used from the database of the Protein Structures Database (PDB).

Conclusions. As a result of the molecular docking, data were obtained that form an idea of a certain level of probability of the effect of synthesized compounds on the activity of 14α-demethylase lanosterol, which justified the need for further study of antifungal activity.

Author Biographies

S. O. Fedotov, Zaporizhzhia State Medical University, Ukraine

PhD-student of the Department of Natural Sciences for Foreign Students and Toxicological Chemistry

A. S. Hotsulia, Zaporizhzhia State Medical University, Ukraine

PhD, DSc, Associate Professor of the Department of Natural Sciences for Foreign Students and Toxicological Chemistry

O. I. Panasenko, Zaporizhzhia State Medical University, Ukraine

PhD, DSc, Professor, Head of the Department of Natural Sciences for Foreign Students and Toxicological Chemistry

References

Can, N. Ö., Acar Çevik, U., Sağlık, B. N., Levent, S., Korkut, B., Öz-kay, Y., & Koparal, A. S. (2017). Synthesis, molecular docking studies, and antifungal activity evaluation of new benzimidazole-triazoles as potential lanosterol 14α-demethylase inhibitors. Journal of Chemistry, 2017. Article ID 9387102. https://doi.org/10.1155/2017/9387102

Othman, A. A., Kihel, M., & Amara, S. (2019). 1,3,4-Oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole derivatives as potential antibacterial agents. Arabian Journal of Chemistry, 12(7), 1660-1675. https://doi.org/10.1016/j.arabjc.2014.09.003

Shcherbyna, R., Panasenko, O., Polonets, O., Nedorezanıuk, N. & Duchenko, M. (2021). Synthesis, antimicrobial and antifungal activity of ylidenhydrazides of 2-((4-R-5-R1-4Н-1,2,4-triazol-3-yl)thio)acetaldehydes. Journal of Faculty of Pharmacy of Ankara University, 45(3), 504-514. https://doi.org/10.33483/jfpau.939418

Yaroshenko, A. A., Parchenko, V. V., Bihdan, O. A., Panasenko, O. I., Karpenko, Y. V., & Karpun, E. O. (2021). Method for Trifuzol-neo assay determination by GC-MS. Research Journal of Pharmacy and Technology, 14(9), 4523-4528. https://doi.org/10.52711/0974-360X.2021.00787

Safonov, A. (2020). Method of synthesis novel N'-substituted 2-((5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazides. Journal of Faculty of Pharmacy of Ankara University, 44(2), 242-252. https://doi.org/10.33483/jfpau.580011

Frolova, Y., Kaplaushenko, A., & Nagornaya, N. (2020). Design, synthesis, antimicrobial and antifungal activities of new 1,2,4-triazole derivatives containing 1H-tetrazole moiety. Journal of Faculty of Pharmacy of Ankara University, 44(1), 70-88. https://doi.org/10.33483/jfpau.574001

Samelyuk, Y. G., & Kaplaushenko, A. G. (2014). Synthesis of 3-alkylthio(sulfo)-1,2,4-triazoles, containing methoxyphenyl substituents at C5atoms, their antipyretic activity, propensity to adsorption and acute toxicity. Journal of Chemical and Pharmaceutical Research, 6(5), 1117-1121.

Safonov, A. A., Nevmyvaka, A. V., Panasenko, O. I., & Knysh, Y. G. (2021). Microwave synthesis of 3- and 4-substituted-5-((3-phenylpropyl)thio)-4H-1,2,4-triazoles. Ankara Universitesi Eczacilik Fakultesi Dergisi, 45(3), 457-466. https://doi.org/10.33483/jfpau.902274

Varynskyi, B., Kaplaushenko, A., & Parchenko, V. (2018). Electrospray ionization mass spectrometry fragmentation pathways of salts of some 1,2,4-triazolylthioacetate acids, the active pharmaceutical ingredients. Asian Journal of Pharmaceutical and Clinical Research, 11(10), 303-312. https://doi.org/10.22159/ajpcr.2018.v11i10.16564

Gotsulya, A., Zaika, Y., Brytanova, T. (2022). Synthesis, properties and biological potential some condensed derivatives 1,2,4-triazole. Journal of Faculty of Pharmacy of Ankara University, 46(2), 308-321. https://doi.org/10.33483/jfpau.971602

Ismail, M., Mohamady, S., Samir, N., Abouzid, K. (2020). Design, synthesis, and biological evaluation of novel 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine inhibitors as antitumor agents. ACS Omega, 5, 20170-20176. https://doi.org/10.1021/acsomega.0c01829

Gotsulya, A. S. (2020). Synthesis and antiradical activity of alkyl derivatives of 5-(5-methyl-1H-pyrazol-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol. Journal of Faculty of Pharmacy of Ankara University, 44(2), 211-219. https://doi.org/10.33483/jfpau.616116

Fedotov, S. O., & Hotsulia, А. S. (2021). Synthesis and properties of S-derivatives of 4-amino-5-(5-methylpyrazol-3-yl)-1,2,4-triazole-3-thiol. Current issues in pharmacy and medicine: science and practice, 14(3), 268-274. https://doi.org/10.14739/2409-2932.2021.3.243176

Boraei, A., Ghabbour, H., Gomaa, M., El Ashry, E., & Barakat, A. (2019). Synthesis and anti-proliferative assessment of triazolo-thiadiazepine and triazolo-thiadiazine scaffolds. Molecules, 24, 4471-4480. https://doi.org/10.3390/molecules24244471

Sonawane, R., & Mohite, S. (2021). Heterocyclic bridgehead Nitrogen atom system: review on [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and its pharmacological screening. Asian journal of research in chemistry, 14(3), 217-220. https://doi.org/10.52711/0974-4150.2021.00038

Biovia. (2019). Discovery Studio Visualizer, v 19.1.0.18287 [Software]. Retrieved from http://www. 3dsbiovia.com/

ChemAxon. (2015). MarvinSketch, Version 6.3.0. [Software]. Retrieved from http://www.chemaxon.com

Worldwide Protein Data Bank. (n.d.). Protein Data Bank (PDB) [Database]. Retrieved from http://www.pdb.org

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Published

2022-08-01

How to Cite

1.
Fedotov SO, Hotsulia AS, Panasenko OI. Synthesis and properties of some 3-(5-(4-methoxyphenyl)pyrazol-3-yl)-6-R-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles. Current issues in pharmacy and medicine: science and practice [Internet]. 2022Aug.1 [cited 2024May24];15(2):117-22. Available from: http://pharmed.zsmu.edu.ua/article/view/259227

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Original research