Synthesis methods of 1,2,4-triazole-3-thiones: review

Authors

DOI:

https://doi.org/10.14739/2409-2932.2024.2.302616

Keywords:

1,2,4-triazole, physical-chemical properties, transformation

Abstract

1,2,4-Triazole-containing compounds are unique heterocyclic compounds present in an array of pharmaceuticals and biologically important compounds used in drug-discovery studies against cancer cells, microbes, and various types of diseases in the human body.

The aim of the study was to analyze in detail and combine the available literature materials to study the reactions associated with the formation of different classes of derivatives of 1,2,4-triazole-3-thione and to study their physical-chemical properties.

Various innovative methods have been proposed and explored for synthesizing different classes of 1,2,4-triazole compounds, each with distinct applications and potential medicinal benefits. When analyzing the outcomes of studies aimed at obtaining new 1,2,4-triazole-3-thiones, it’s crucial to recognize the multiple stages involved in their synthesis. These stages typically include the esterification of carboxylic acids, hydrazinolysis, the formation of carbothioamides, and thiones through alkaline cyclization. Subsequently, reactions involving the S-function are conducted, leading to the formation of various classes of derivatives of 1,2,4-triazole.

The study by a team of scientists introduced a novel method for synthesizing imidazolyl- and imidazole-1,2,4-triazoles, targeting the design of safer analgesic and anti-inflammatory agents.

Moreover, researchers have successfully synthesized derivatives of 3-[2-(5-thio-4-aryl-4H-1,2,4-triazole-3-yl)ethyl]quinoxalin-2(1H)-one, N-(3-thio-5-aryl-[1,2,4]triazole-4-yl)acylamides, 5-alkylthio-4-amino-3-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-1,2,4-triazole and 3-(5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-thiomethyl)-6-aryl-5,6-dihydrogen-1,2,4-triazole-[3,4-b]-1,3,4-thiadiazole, 5,5’-(alkyldiyl-bis(sulfandiyl))bis(N-(arylidene)-3-thiophen-2-ylmethyl)-4H-1,2,4-triazole-4-amines, 3-(arylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole, expanding the scope of 1,2,4-triazole-based, compounds with potential pharmacological activities. Furthermore, the synthesis of molecules containing two 1,2,4-triazole and two benzole rings has gained traction, offering new avenues for drug development.

Mannich bases were synthesized from the corresponding thiones through a reaction with N-methylpiperazine or N-phenylpiperazine in dimethylformamide in the presence of formaldehyde.

Additionally, the synthesis of salts derived from 1,2,4-triazole highlights its importance in pharmaceutical formulations, with studies focusing on both organic and inorganic salts for potential therapeutic applications.

Conclusions. The analysis of the above-mentioned publications indicates that the search for new biologically active compounds among derivatives of 1,2,4-triazole-3-thiones is promising. Many 1,2,4-triazole-3-thiones exhibit a wide spectrum of biological activity with little toxicity.

Author Biographies

Yu. S. Frolova , Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, Assistant of the Department of Physical and Colloidal Chemistry

A. H. Kaplaushenko, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, DSc, Professor of the Department of Physical and Colloidal Chemistry

T. V. Ihnatova, Private Higher Educational Institution “Pylyp Orlyk International Classical University”, Mykolaiv, Ukraine

PhD, Associate Professor, Dean of the Faculty of Health Care

T. M. Kaplaushenko, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, Lecturer, Medical College

References

Samelyuk Y, Kaplaushenko A. 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. 2014:6(5):1117-21. Available from: https://www.jocpr.com/articles/synthesis-of-3alkylthiosulfo124triazoles-containing-methoxyphenyl-substituents-at-c5-atoms-their-antipyretic-activity-pr.pdf

Varynskyi BA, Scherback MA, Kaplaushenko AG, Yurchenko IA. The study of thione-thiol tautomerism of 4-amino-5-(4-nitrophenyl)- 2,4-dihydro-3H-1,2,4-triazole-3-thione by HPLC-MS method. Journal of Chemical and Pharmaceutical Research 2019;6(5):1342-50. Available from: https://www.jocpr.com/articles/the-study-of-thionethiol-tautomerism-of-4amino54nitrophenyl-24dihydro3h124triazole3thione-by-hplcms-method.pdf

Safonov A. Derivatives of 3-(alkylthio)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-4-amines as increasing efficiency substances. Indonesian Journal of Pharmacy 2018;29(3):167.

Dovbnia D, Frolova Y, Kaplaushenko A. A study of hypoglycemic activity of acids and salts containing 1,2,4-triazole. Ceska Slov Farm. 2023;72(3):113-24. English.

Shcherbyna R. Microwave-assisted synthesis of some new derivatives of 4-substituted-3-(morpholinomethyl)-4H-1,2,4-triazole-5-thioles. Ankara Universitesi Eczacilik Fakultesi Dergisi 2019;43(3):220-9. doi: https://doi.org/10.33483/jfpau.533166

Ihnatova T, Kaplaushenko A, Frolova Y, Pryhlo E. Synthesis and antioxidant properties of some new 5-phenethyl-3-thio-1,2,4-triazoles. Pharmacia. 2020;68(1):129-33. doi: https://doi.org/10.3897/pharmacia.68.e53320

Safonov A. 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. 2020;44(2):242-52. doi: https://doi.org/10.33483/jfpau.580011

Shcherbyna R, Panasenko O, Polonets O, Nedorezaniuk N, Duchenko M. 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. 2021;45(3):504-14. doi: https://doi.org/10.33483/jfpau.939418

Frolova Y, Kaplaushenko A, Sameliuk Y, Romanina D, Morozova L. Investigation of the antimicrobial and antifungal activities of some 1,2,4-triazole derivatives. Ceska Slov Farm. 2022;71(4):151-60. English.

Toropin NV, Trush YV, Murashevich BV, Burmistrov KS. Synthesis of 1-(hydroxylphenyl)-3-aryl-5-mercapto-1,2,4-triazoles from arenalazine quinones. Voprosy khimii i khimicheskoi tekhnologii. 2019;2:46-50. Available from: http://vhht.dp.ua/wp-content/uploads/pdf/2018/2/Toropin.pdf

Hassan AA, Mohamed NK, Aly AA, Tawfeek HN, Bräse S, Nieger M. Eschenmoser‐Coupling Reaction Furnishes Diazenyl‐1,2,4‐triazole‐5(4H)‐thione Derivatives. ChemistrySelect. 2019;4(2):465-8. doi: https://doi.org/10.1002/slct.201802870

Akın Ş, Demir EA, Colak A, Kolcuoglu Y, Yildirim N, Bekircan O. Synthesis, biological activities and molecular docking studies of some novel 2,4,5-trisubstituted-1,2,4-triazole-3-one derivatives as potent tyrosinase inhibitors. Journal of Molecular Structure. 2019;1175:280-6. doi: https://doi.org/10.1016/j.molstruc.2018.07.065

Dai J, Tian S, Yang X, Liu Z. Synthesis methods of 1,2,3-/1,2,4-triazoles: A review. Front Chem. 2022;10:891484. doi: https://doi.org/10.3389/fchem.2022.891484

Ameen DS, Hamdi MD, Khan AK. Synthesis and Biological Activities of Some 1,2,4-Triazole Derivatives: A Review. Al Mustansiriyah Journal of Pharmaceutical Sciences 2022;22(3):65-81. doi: https://doi.org/10.32947/ajps.v22i3.890

Guo MB, Yan ZZ, Wang X, Xu H, Guo C, Hou Z, et al. Design, synthesis and antifungal activities of novel triazole derivatives with selenium-containing hydrophobic side chains. Bioorg Med Chem Lett. 2022;78:129044. doi: https://doi.org/10.1016/j.bmcl.2022.129044

Emami L, Sadeghian S, Mojaddami A, Khabnadideh S, Sakhteman A, Sadeghpour H, et al. Design, synthesis and evaluation of novel 1,2,4-triazole derivatives as promising anticancer agents. BMC Chem. 2022;16(1):91. doi: https://doi.org/10.1186/s13065-022-00887-x

Wittine K, Stipković Babić M, Makuc D, Plavec J, Kraljević et al. Novel 1,2,4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-HCV and antitumor activity evaluations. Bioorg Med Chem. 2012;20(11):3675-85. doi: https://doi.org/10.1016/j.bmc.2012.01.054

Almasirad A, Mousavi Z, Tajik M, Assarzadeh MJ, Shafiee A. Synthesis, analgesic and anti-inflammatory activities of new methyl-imidazolyl-1,3,4-oxadiazoles and 1,2,4-triazoles. Daru. 2014;22(1):22. doi: https://doi.org/10.1186/2008-2231-22-22

Tariq S, Alam O, Amir M. Synthesis, anti-inflammatory, p38α MAP kinase inhibitory activities and molecular docking studies of quinoxaline derivatives containing triazole moiety. Bioorg Chem. 2018;76:343-58. doi: https://doi.org/10.1016/j.bioorg.2017.12.003

Bulut N, Kocyigit UM, Gecibesler IH, Dastan T, Karci H, Taslimi P, et al. Synthesis of some novel pyridine compounds containing bis-1,2,4-triazole/thiosemicarbazide moiety and investigation of their antioxidant properties, carbonic anhydrase, and acetylcholinesterase enzymes inhibition profiles. J Biochem Mol Toxicol. 2018;32(1). doi: https://doi.org/10.1002/jbt.22006

Bekircan O, Ülker S, Menteşe E. Synthesis of some novel heterocylic compounds derived from 2-[3-(4-chlorophenyl)-5-(4-methoxybenzyl)-4H-1,2,4-triazol-4-yl]acetohydrazide and investigation of their lipase and α-glucosidase inhibition. J Enzyme Inhib Med Chem. 2015;30(6):1002-9. doi: https://doi.org/10.3109/14756366.2014.1003213

Karaca Gençer H, Acar Çevik U, Levent S, Sağlık BN, Korkut B, Özkay Y, et al. New Benzimidazole-1,2,4-Triazole Hybrid Compounds: Synthesis, Anticandidal Activity and Cytotoxicity Evaluation. Molecules. 2017;22(4):507. doi: https://doi.org/10.3390/molecules22040507

Holota S, Shylych Y, Derkach H, Karpenko O, Gzella A, Lesyk R. Synthesis of 4-(2h-[1,2,4]-triazol-5-ylsulfanyl)-1,2-dihydropyrazol-3-one via ring-switching hydrazinolysis of 5-ethoxymethylidenethiazolo [3,2-b][1,2,4]triazol-6-one. MolBank. 2018;2018(4). doi: https://doi.org/10.3390/M1022

Rud AM, Kaplaushenko AG, Yurchenko IO. Synthesis, physical and chemical properties of 2-((5-(hydroxy(phenyl)methyl)-4R-4H-1,2,4-triazole-3-yl)thio)acetic acids and its salts. Zaporozhye medical journal 2018;20(1):105-9. doi: https://doi.org/10.14739/2310-1210.2018.1.122126

Pruglo Y. Synthesis, physical and chemical properties and anxiolytic activity OF 2-(4-(R-arylidenamino)-5-methyl-4H-1,2,4-triazole-3-YL)thio)acetic acids and their salts. ScienceRise: Pharmaceutical Science. 2018;(3):19-25. doi: https://doi.org/10.15587/2519-4852.2018.135786

Shcherbyna R, Parchenko V, Varynskyi B, Kaplaushenko A. The development of HPLC-DAD method for determination of active pharmaceutical ingredient in the potassium 2-((4-amino-5-(morpholinomethyl)-4H-1,2,4-triazol-3-yl)thio) acetate substance. Current Issues in Pharmacy and Medical Sciences. 2019;32(1):5-9. doi: https://doi.org/10.2478/cipms-2019-0001

Shcherbyna R. An investigation of the pharmacokinetics and potential metabolites of potassium 2-((4-amino-5-(morfolinometyl)-4H-1,2,4-triazol-3-yl)thio) acetate on rats. Journal of Faculty of Pharmacy of Ankara University. 2020;44(2):233-41. doi: https://doi.org/10.33483/jfpau.681611

Safonov A, Demianenko D, Vashchyk Y, Larianovska Y, Lytkin D, Shcherbyna R, et al. Histological study of a corrective influence of sodium 2-((4-amino-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio) acetate on the state of rats liver under conditions of acute immobilization stress. Ankara Universitesi Eczacilik Fakultesi Dergisi. 2022;46(2):330-41. doi: https://doi.org/10.33483/jfpau.1012893

Pogrebnoi S, Radul O, Stingaci E, Lupascu L, Valica V, Uncu L, et al. The Synthesis of Triazolium Salts as Antifungal Agents: A Biological and In Silico Evaluation. Antibiotics (Basel). 2022;11(5):588. doi: https://doi.org/10.3390/antibiotics11050588

Pruglo YS. [Synthesis and study of physical-chemical properties of salts of 2-(5-(2-bromophenyl)-4-amino-4H-1,2,4-triazole-3-ylthio)acetic acid]. Current issues in pharmacy and medicine: science and practice. 2018;11(1):12-6. Ukrainian. doi: https://doi.org/10.14739/2409-2932.2018.1.123588

Xu W, Song B, Bhadury P, Song Y, Hu D. Synthesis and crystal structure of novel sulfone derivatives containing 1,2,4-triazole moieties. Molecules. 2010;15(2):766-79. doi: https://doi.org/10.3390/molecules15020766

Rud AM, Kaplaushenko AG, Samеliuk YG. [Synthesis of new alkylsulfonyl(Sulfinyl)-1,2,4-triazole derivatives based on (3-(Alkylthio)-4-R-1,2,4-thriazole-5-yl)(phenyl)methanol’s]. Current issues in pharmacy and medicine: science and practice. 2018;11(1):23-8. Ukrainian. doi: https://doi.org/10.14739/2409-2932.2018.1.123641

Siddoju K, Ega JK. Stepwise synthesis and characterization of newly synthesized 1,2,4-triazole derivatives. International journal of pharmaceutical, chemical and biological sciences. 2018;8(1):139-46. Available from: https://www.ijpcbs.com/articles/stepwise-synthesis-and-characterization-ofnewly-synthesized-124triazole-derivatives.pdf

Kareem MM. Synthesis, characterization and study the physical properties of new 1,2,4-Triazoles Mannich-Base derivatives. IOP Conf Ser Mater Sci Eng. 2018;454(1):012092. doi: https://doi.org/10.1088/1757-899X/454/1/012092

Liu ZM, Chen Q, Chen CN, Tu HY, Yang GF. Syntheses of diheterocyclic compounds based on 2-thioacetohydrazide-5,7-dimethyl-1,2,4-triazolo[1,5-a]- pyrimidine. Molecules. 2008;13(6):1353-60. doi: https://doi.org/10.3390/molecules13061353

Safonov AA. Synthesis of novel 5,5’-(R-diylbis(sulfanediyl))bis(3-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-4-amines). Ukraïns’kij bìofarmacevtičnij žurnal. 2018;0(1):51-4. doi: https://doi.org/10.24959/ubphj.18.154

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Published

2024-06-14

How to Cite

1.
Frolova YS, Kaplaushenko AH, Ihnatova TV, Kaplaushenko TM. Synthesis methods of 1,2,4-triazole-3-thiones: review. Current issues in pharmacy and medicine: science and practice [Internet]. 2024Jun.14 [cited 2024Jul.21];17(2):187-96. Available from: http://pharmed.zsmu.edu.ua/article/view/302616