Synthesis and study of the anticancer activity of some new 7H-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazines

Authors

DOI:

https://doi.org/10.14739/2409-2932.2021.3.240361

Keywords:

organic synthesis, NMR spectroscopy, triazolo[3,4-b][1,3,4]thiadiazines, anticancer activity

Abstract

The problem of finding effective low-toxic anticancer agents is one of the most important in modern medicine and pharmacy. Despite a large selection of anticancer drugs and a variety of mechanisms of their action, the effectiveness of existing drugs continues to be insufficient. Among the numerous natural and synthetic heterocyclic compounds that exhibit anticancer activity, 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives, which are able to initiate different pathways of tumor cell death. Based on this, the synthesis of new derivatives of this class of compounds and the study of their anticancer properties is relevant.

The aim of the work is to synthesis of new 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and study their anticancer activity.

Materials and methods. It was used methods of organic synthesis, physical and chemical methods of analysis organic compounds (1H NMR spectroscopy, elemental analysis).

Results. In order to obtain new 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, the interaction implemented of 4-amino-4H-[1,2,4]triazole-3-thiols with the corresponding bromoacetophenones. The reaction proceeds by heating the above reagents in alcohol with the closure of the thiadiazine ring and the formation of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine systems. The structure of all synthesized compounds was confirmed by 1H NMR spectroscopy and elemental analysis data.

The study of the anticancer activity of the synthesized compounds was carried out in the framework of the international scientific program DTP (Developmental Therapeutics Program) of the National Cancer Institute (NCI, Bethesda, Maryland, USA). It was found that the synthesized compounds exhibited different levels of anticancer activity. The most active among the tested substances was compound 3j with an average GP value of 28.73. The most sensitive to it were the lines of melanoma MDA-MB-435 and SK-MEL-2, kidney cancer A498 and RXF 393, CNS cancer SNB-75, and non-small cell lung cancer NCI-H522. The secondary stage of studies of this compound confirmed its high anticancer activity against most cancer cell lines.

Conclusions. As a result of the interaction of 4-amino-4H-[1,2,4]triazole-3-thiols with the relevant bromoacetophenones, a series of new triazolo[3,4-b][1,3,4]thiadiazines was not described in the literature was synthesized. Testing the synthesized compounds for the antitumor activity made it possible to isolate 1 highly active compound with a pronounced anticancer effect, which in terms of activity approaches or exceeds the known drugs 5-fluorouracil (5-FU) and cisplatin, as well as an anticancer agent, curcumin.

 

Author Biographies

I. I. Myrko, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

Assistant of the Department of General, Bioinorganic, Physical and Colloidal Chemistry

T. I. Chaban, Danylo Halytsky Lviv National Medical University, Ukraine

PhD, Associate Professor of the Department of General, Bioinorganic, Physical and Colloidal Chemistry

V. V. Ohurtsov, Danylo Halytsky Lviv National Medical University, Ukraine

PhD, Associate Professor of the General, Bioinorganic, Physical and Colloidal Chemistry

I. V. Drapak, Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

DSc, Professor, Head of the Department of General, Bioinorganic, Physical and Colloidal Chemistry

V. S. Matiichuk, Ivan Franko National University of Lviv, Lviv, Ukraine

DSc, Professor of the Department of Organic Chemistry

References

Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a cancer journal for clinicians, 71(3), 209-249. https://doi.org/10.3322/caac.21660

Schirrmacher V. (2019). From chemotherapy to biological therapy: A review of novel concepts to reduce the side effects of systemic cancer treatment (Review). International journal of oncology, 54(2), 407-419. https://doi.org/10.3892/ijo.2018.4661

Al-Mulla, A. (2017). A Review: Biological Importance of Heterocyclic Compounds. Der Pharma Chemica, 9(13), 141-147.

Kerru, N., Gummidi, L., Maddila, S., Gangu, K. K., & Jonnalagadda, S. B. (2020). A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications. Molecules, 25(8), 1909. https://doi.org/10.3390/molecules25081909

Ismail, M. I., 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(32), 20170-20186. https://doi.org/10.1021/acsomega.0c01829

Tardito, S., Bussolati, O., Maffini, M., Tegoni, M., Giannetto, M., Dall'asta, V., Franchi-Gazzola, R., Lanfranchi, M., Pellinghelli, M. A., Mucchino, C., Mori, G., & Marchio, L. (2007). Thioamido coordination in a thioxo-1,2,4-triazole copper(II) complex enhances nonapoptotic programmed cell death associated with copper accumulation and oxidative stress in human cancer cells. Journal of medicinal chemistry, 50(8), 1916-1924. https://doi.org/10.1021/jm061174f

Kamel, M. M., & Megally Abdo, N. Y. (2014). Synthesis of novel 1,2,4-triazoles, triazolothiadiazines and triazolothiadiazoles as potential anticancer agents. European journal of medicinal chemistry, 86, 75-80. https://doi.org/10.1016/j.ejmech.2014.08.047

Mohamady, S., Gibriel, A. A., Ahmed, M. S., Hendy, M. S., & Naguib, B. H. (2020). Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB. Bioorganic chemistry, 96, 103641. https://doi.org/10.1016/j.bioorg.2020.103641

Bhatia, R., Rathore, P., & Nayak, S. (2012). Synthesis, characterization and anti-inflammatory activity of 1,2,4 triazole derivatives. Current Research in Pharmaceutical Sciences, 2(3), 160-165.

Song, M.-X., Zhang, C.-B., Deng, X.-Q., Sun, Z.-G., & Quan, Z.-S. (2011). Synthesis and anticonvulsant activity evaluation of 6-phenyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines. Letters in Drug Design & Discovery, 8(8), 769-773. https://doi.org/10.2174/157018011796575962

Prakash, O., Aneja, D. K., Hussain, K., Lohan, P., Ranjan, P., Arora, S., Sharma, C., & Aneja, K. R. (2011). Synthesis and biological evaluation of dihydroindeno and indeno [1,2-e] [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazines as antimicrobial agents. European journal of medicinal chemistry, 46(10), 5065-5073. https://doi.org/10.1016/j.ejmech.2011.08.019

Pundeer, R., Kiran, V., Prakash, R., Subhash, S., Bhatia, C., Sharma, C. & Aneja, K. α,α-Dibromoacetophenones mediated synthesis of some new 7H-7-alkoxy-3-alkyl/phenyl-6-aryl-s-triazolo[3,4-b][1,3,4]thiadiazines and their antimicrobial evaluation. Medicinal Chemistry Research, 21(12), 4043-4052. https://doi.org/10.1007/s00044-011-9945-1

Nayak, S. G., & Poojary, B. (2020). Design, synthesis, in silico docking studies, and antibacterial activity of some thiadiazines and 1,2,4-triazole-3-thiones bearing pyrazole moiety. Russian Journal of Bioorganic Chemistry, 46(1), 97-106. https://doi.org/10.1134/S1068162020010069

Myrko, I. I., Chaban ,T. I., Ogurtsov, V. V., & Matiychuk, V. S. (2021). Syntez ta doslidzhennia antymikrobnoi aktyvnosti deiakykh pirazolzamishchenykh 7H-[1,2,4]tryazolo[3,4-b][1,3,4]tiadiazyniv [Synthesis and study of antimicrobial activity of some pyrazole-substituted 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines]. Farmatsevtychnyy chasopys, (1), 5-13. [in Ukrainian]. https://doi.org/10.11603/2312-0967.2021.1.11986

Li, Z., Bai, X., Deng, Q., Zhang, G., Zhou, L., Liu, Y., Wang, J. & Wang, Y. (2017). Preliminary SAR and biological evaluation of antitubercular triazolothiadiazine derivatives against drug-susceptible and drug-resistant Mtb strains. Bioorganic & Medicinal Chemistry, 25(1), 213-220. https://doi.org/10.1016/j.bmc.2016.10.027

Niranjan, K., Kumar, N. & Kumar, A. (2015). Synthesis of triazolothiadiazine derivatives as antioxidant agents. Journal of Pharmacy and Pharmaceutical Sciences, 7(6), 120-123.

Chaban, T. I., Ohurtsov, V. V., Matiichuk, V. S., Honcharenko, O. V., & Chaban I. H. (2019). Syntez deiakykh novykh N3 zamishchenykh 5-hidroksy-7-metyl-3H-tiazolo[4,5-b]pirydyn-2-oniv yak potentsiinykh biolohichno aktyvnykh rechovyn [Synthesis of some new N3 substituted 5-hydroxy-7-methyl-3H-thiazolo[4,5-b]pyridin-2-ones as potential biologically active substances]. Current issues in pharmacy and medicine: science and practice, 12(2), 129-134. [in Ukrainian]. https://doi.org/10.14739/2409-2932.2019.2.170974

Myrko, I., Chaban, T., Matiichuk, Y., Arshad, M. & Matiychuk, V. (2021). Approaches for the synthesis, chemical modification and biological properties of n-acylphenothiazines. Current Chemistry Letters, 10(4), 377-392. https://doi.org/10.5267/j.ccl.2021.5.005

Chaban, T. I., Matiichuk, Y. E., Shyyka, O. Y., Chaban, I. G., Ogurtsov, V. V., Nektegayev, I. A., & Matiychuk, V. S. (2020). Synthesis, Molecular Docking and Biological Properties of Novel Thiazolo[4,5-b]pyridine Derivatives. Acta chimica Slovenica, 67(4), 1035-1043. http://dx.doi.org/10.17344/acsi.2019.5439

Chaban, T., Matiichuk, Y., Сhulovska, Z., Tymoshuk, O., Chaban, I. & Matiychuk, V. (2021) Synthesis and biological evaluation of new 4-oxo-thiazolidin-2-ylidene derivatives as antimicrobial agents. Archiv der pharmazie, 354(7), e2100037. https://doi.org/10.1002/ardp.202100037

Mndjoyan A. L. (1960). Syntezy heterotsyklycheskykh soedynenyi. Vypusk 5. [Synthesis of heterocyclic compounds (Vol. 5)]. Erevan: AN ArmSSR. [in Russian].

Developmental Therapeutics Program. Available online: http://dtp.nci.nih.gov

Published

2021-10-25

How to Cite

1.
Myrko II, Chaban TI, Ohurtsov VV, Drapak IV, Matiichuk VS. Synthesis and study of the anticancer activity of some new 7H-[1,2,4]triazolo [3,4-b][1,3,4]thiadiazines. Current issues in pharmacy and medicine: science and practice [Internet]. 2021Oct.25 [cited 2024Jul.20];14(3):320-7. Available from: http://pharmed.zsmu.edu.ua/article/view/240361

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Original research