Synthesis and properties of 6-(2,6-dichlorophenyl)-3- (3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazine-7-carboxylic acid and its salts




1,2,4-triazole, pyrazole, properties, in silico research


Carboxylic acids and their derivatives are an important component of many biological processes. For example, they can be used to create new medicines that can be useful in the fight against various diseases. Additionally, compounds containing a thiazole moiety may possess beneficial properties in practical pharmacy. The incorporation of this heterocyclic structure in molecules can positively impact several biological characteristics, such as anti-inflammatory, antiviral, and antifungal activities.

Consequently, exploring novel compounds that combine a thiazole fragment with a carboxyl group holds promise for the advancement of new drugs and diagnostic tools that can contribute significantly to the battle against numerous diseases.

The aim of the work was to create a number of organic and inorganic salts of 6-(2,6-dichlorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid and study of their properties, as well as selective determination of the biological potential of these compounds.

Materials and methods. The synthetic part of the study involved the sequential synthesis of the original compound 4-amino-5-(3-methyl-1H-pyrazol-5-yl)-1,2,4-triazole-3-thiol using a well-established method described in previous articles. The next stage involved the reaction of thiol with 2,3-dichlorobenzaldehyde in a medium of glacial acetic acid. The resulting Schiff base was subsequently reacted with 2-chloroethanoic acid in tetrahydrofuran in the presence of an equimolar amount of sodium hydride.

Salts of the corresponding acid were formed during the reaction of 6-(2,6-dichlorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid with both organic and inorganic bases in an aqueous-alcohol medium. The structures of all synthesized compounds were determined using 1H NMR spectroscopy and elemental analysis. Additionally, the individuality of each compound was confirmed using high-performance liquid chromatography-mass spectrometry.

Results. The study determined the optimal conditions for the formation of both organic and inorganic salts of 6-(2,6-dichlorophenyl)-3-(3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid. The analysis of pharmacokinetic parameters and physicochemical properties using ADME (absorption, distribution, metabolism, and excretion) allowed for the identification of promising synthesized compounds and the selection of more optimal compounds for further investigation.

Conclusions. The structure of 12 compounds was synthesized and confirmed. Physical-chemical and pharmacokinetic analysis of ADME parameters was carried out and promising compounds were selected for more in-depth research.

Author Biographies

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

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

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

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


Fedotov S. O., & Hotsulia A. S. (2022). Synthesis and properties of 3-(ethylthio)-9-methyl-6-(alkylthio) pyrazolo[1,5-d][1,2,4]triazolo[3,4-f][1,2,4]triazines. Current issues in pharmacy and medicine: science and practice, 15(3), 227-234.

Voskoboynik, O. Y., Kolomoets, O. S., Kovalenko, S. I., & Shishkina, S. V. (2017). [1,2,4]Triazino[2,3-с]quinazolines 1. Methods for the preparation and spectral characteristics of substituted 3-R1-6-R3-6,7-dihydro-2H-[1,2,4]triazino[2,3-с]quinazolin-2-ones. Chemistry of Heterocyclic Compounds, 53(8), 892-904.

Voskoboinik, O. Y., Stavytskyi, V. V., Antypenko, O. M., Kazunin, M. S., Kravtsov, D. V., Shishkina, S. V., & Kovalenko, S. I. (2020). Synthesis and structure of pyrido[1,2-a]quinazoline condensed derivatives. Synthetic Communications, 50(13), 2043-2051.

Can, N. Ö., Acar Çevik, U., Saǧlik, B. N., Levent, S., Korkut, B., Özkay, Y., Kaplancikli Z., & 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.

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. Ankara Universitesi Eczacilik Fakultesi Dergisi, 45(3), 504-514.

Chaban, Z., Harkov, S., Chaban, T., Klenina, O., Ogurtsov, V., & Chaban, I. (2017). Recent advances in synthesis and biological activity evaluation of condensed thiazoloquinazolines: A review. Pharmacia, 64(3), 52-66.

Аleksandrova, K. V., Levich, S. V., Mykhalchenko, Ye. K., & Sinchenko, D. M. (2016). Synthesis and physical-chemical properties of 3-aryl-(aralkyl)-8-hydrazinemethylxanthines and their N-substituted derivatives. Current issues in pharmacy and medicine: science and practice, (2), 26-31.

Li, Y. S., Tian, H., Zhao, D. S., Hu, D. K., Liu, X. Y., Jin, H. W., Song, G. P., & Cui, Z. N. (2016). Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors. Bioorganic & medicinal chemistry letters, 26(15), 3632-3635.

Suhak, O. A., Panasenko, O. I., Knysh, Ye. G., & Kamyshny, O. M. (2015). Protymikrobna ta protyhrybkova aktyvnist pokhidnykh 3-(alkiltio)-4-R-5-(tiofen-2-ilmetyl)-4H-1,2,4-triazoliv [Antibacterial and antifungal activity of derivatives 3-(alkylthio)-4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole]. Current issues in pharmacy and medicine: science and practice, (3), 67-70. [in Ukrainian].

Kaplaushenko, A. G. (2013). Doslidzhennia zi stvorennia novoho oryhinalnoho vitchyznianoho likarskoho zasobu na osnovi 1,2,4-triazolu [The Research of Creating a New Original Domestic Drug Based on 1,2,4-triazole]. Naukovyi zhurnal MOZ Ukrainy, (2), 115-121. [in Ukrainian].

Mykhalchenko, Y., Aleksandrova, K., Shkoda, O., & Pruglo, Y. (2019). Prospective biological active compounds among 7-substituted of 3-benzyl-8-propylxanthines for treatment of metabolic syndrome pathologies. Eureka: Health Sciences, (5), 52-58.

Safonov, A. A. (2020). Method of synthesis novel N’-Substituted- 2-((5-(Thiophen-2-Ylmethyl)-4H-1,2,4-Triazol-3-YL)Thio) acetohydrazides. Ankara Universitesi Eczacilik Fakultesi Dergisi, 44(2), 242-252.

Karpenko, Y., Omelyanchik, L., & Panasenko, T. (2018). Experimental and theoretical spectroscopic study of thione-thiol tautomerism of new hybrides 1,3,4-oxadiazole-2-thion with acridine-9(10h)-one. Chemistry and Chemical Technology, 12(4), 419-428.

Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific reports, 7, 42717.

Lovering, F., Bikker, J., & Humblet, C. (2009). Escape from flatland: increasing saturation as an approach to improving clinical success. Journal of medicinal chemistry, 52(21), 6752-6756.

Moriguchi, I., Hirono, S., Liu, Q., Nakagome, Izum., & Matsushita, Y. (1992). Simple Method of Calculating Octanol/Water Partition Coefficient. Chemical and Pharmaceutical Bulletin, 40(1), 127-130.

Cheng, T., Zhao, Y., Li, X., Lin, F., Xu, Y., Zhang, X., Li, Y., Wang, R., & Lai, L. (2007). Computation of octanol-water partition coefficients by guiding an additive model with knowledge. Journal of chemical information and modeling, 47(6), 2140-2148.

Potts, R. O., & Guy, R. H. (1992). Predicting skin permeability. Pharmaceutical research, 9(5), 663-669.




How to Cite

Fedotov SO, Hotsulia AS. Synthesis and properties of 6-(2,6-dichlorophenyl)-3- (3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazine-7-carboxylic acid and its salts. Current issues in pharmacy and medicine: science and practice [Internet]. 2023Jul.3 [cited 2024May24];16(2):121-9. Available from:



Original research