DOI: https://doi.org/10.15587/2519-4852.2018.135786

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

Yevgean Pruglo

Abstract


It is estimated that 50% of all molecules of medicinal products used in drug therapy are administered as salts. This fact indicates that formation of a medicinal substance salt is an important stage in the development of a medicinal remedy.

Therefore, we believe that the combinatorial synthesis of organic and inorganic salts of derivatives of 1,2,4-triazole has not only theoretical but also practical significance.

The aim of the work is to synthesize and establish the structure of new 2-((4-(R-arylidenamino)-5-methyl-4H-1,2,4-triazole-3-yl)thio)acetic acids and their salts, where R is 2H, 4-dimethylaminobenzyliden, 2-hydroxybenzyliden, 4-hydroxybenzyliden, 4-nitrobenzyliden and their anxiolytic activity.

Materials and methods of research. The physical and chemical properties of the obtained compounds were examined according to the methods presented in the State Pharmacopoeia of Ukraine. The melting temperature was determined on an automatic melting device OptiMelt Stanford Research Systems MPA100 (US production). The elemental composition of the compounds was installed on the elemental analyzer Elementar Vario EL cube (CHNS) (standard - sulfanilamide). Chromatographic mass spectral studies were performed on a gas-liquid chromatograph Agilent 1260 Infinity HPLC equipped with an Agilent 6120 mass spectrometer (ionization in an electrical spray (ESI), 1H NMR spectra were recorded on a Mercury 400 spectrometer, DMSO-D6 solvent, internal standard - tetramethylsilane.

Anxiogenic and anxiolytic activities of the studied compounds in the S. Pellow test.

Research results. 4-(R-arylideneamino)-5-methyl-4H-1,2,4-triazole-3-thiols were taken as initial materials, where R was 2H, 4-dimethylaminobenzylidene, 2-hydroxybenzylidene, 4-hydroxybenzylidene, 4-nitrobenzylidene.

Synthesis of 4-(R-arylideneamino)-5-methyl-4H-1,2,4-triazole-3-thiols, where R was 4-dimethylaminobenzylidene, 2-hydroxybenzylidene, 4-hydroxybenzylidene, 4-nitrobenzylidene, was conducted by adding aromatic aldehyde (4-dimethylaminobenzaldehyde, 2-hydroxybenzaldehyde, 4-hydroxybenzaldehyde, 4-nitrobenzaldehyde) to 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol in acetate acid and heated to dissolution of sediment.

The preparation of 2-((4-(R-arylidenamino)-5-methyl-4H-1,2,4-triazole-3-yl)thio)acetic acids was carried out by adding an aromatic aldehyde to an equivalent amount of 2-((4-amino)-5-methyl-4H-1,2,4-triazole-3-yl)thio)acetic acid in acetic acid medium when heated.

Conclusions. A series of new 2-((4-(R-arylidenamino)-5-methyl-4H-1,2,4-triazole-3-yl)thio)acetic acids were synthesized. The structure of synthesized compounds was established using modern physical and chemical methods of analysis. Some physical and chemical properties of the obtained substances were researched

Keywords


1;2;4-triazole; 1HNMR; synthesis; heterocyclic compounds

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References


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Bai, Y., Zhao, G., Li, C., Zhao, S., Shi, Z. (2008). Microwave-Enhanced Reactions of 4-Amino-5-merecapto-1,2,4-triazoles with Benzoyl Chloride and Aromatic Aldehydes. Synthetic Communications, 38 (19), 3311–3319. doi: http://doi.org/10.1080/00397910802136649

Pruglo, Ye. S., Panasenko, O. I., Knysh, Ye. G. (2017). Anxiolytic activity of 4-amino-5-methyl-4H-1,2,4-triazole-3-thion N-derivatives and 2-(4-amino-5-methyl-1,2,4-triazole-3-ylthio) acetic acid salts. Farmacom, 2, 24–29.

George, T., Mehta, D. V., Tahilramani, R., David, J., Talwalker, P. K. (1971). Synthesis of some s-triazoles with potential analgesic and antiinflammatory activities. Journal of Medicinal Chemistry, 14 (4), 335–338. doi: http://doi.org/10.1021/jm00286a016


GOST Style Citations


Bhattachar S. N., Deschenes L. A., Wesley J. A. Solubility: it's not just for physical chemists // Drug Discovery Today. 2006. Vol. 11, Issue 21-22. P. 1012–1018. doi: http://doi.org/10.1016/j.drudis.2006.09.002 

The influence of salt formation on electrostatic and compression properties of flurbiprofen salts / Šupuk E., Ghori M. U., Asare-Addo K., Laity P. R., Panchmatia P. M., Conway B. R. // International Journal of Pharmaceutics. 2013. Vol. 458, Issue 1. P. 118–127. doi: http://doi.org/10.1016/j.ijpharm.2013.10.004 

Kumar L., Amin A., Bansal A. K. Salt selection in drug development // Pharmaceutical Technology. 2008. Vol. 32, Issue 3. P. 128–146.

Shcherbyna R. О. Synthesis, physical and chemical properties of 2-((4-R-3-(morfolinomethylen)-4H-1,2,4-triazole-5-yl)thio)acetic acid salts // Current issues in pharmacy and medicine: science and practice. 2017. Issue 1. P. 4–8. doi: http://doi.org/10.14739/2409-2932.2017.1.93424 

Panasenko O. I., Salionov V. O., Knysh E. G. Derivatives of 3-thio-1,2,4-triazole exhibiting actoprotective activity: Pat. No. 86723 UA. МPK: A61K 31/00, C07D 249/00 / zaiavnyk ta patentovlasnyk Zaporizkyi derzh. med. un-t ta avtory. No. u201308222; declareted: 01.07.2013; published: 10.01.2014, Bul. No. 1.

Odyntsova V. M., Panasenko O. I., Knysh Y. H. Acute toxicity of 2-(5-(adamantane-1-yl)-4R-1,2,4-triazole-3-ylthio) of the acetic acids and their salts’ derivatives // Current issues in pharmacy and medicine: science and practice. 2015. Issue 3. P. 64–66. doi: http://doi.org/10.14739/2409-2932.2015.3.52271 

Sintez i svoystva soley 4,4', 5,5'-tetranitro-1H, 1'H-2,2'-biimidazola – proizvodnykh semikarbazida, 3-amino-1,2,4-triazola i 5-aminotetrazola [Synthesis and properties of 4,4',5,5'-tetranitro-1H,1'H-2,2'-biimidazole salts: semicarbazidium, 3-amino-1,2,4-triazolium, and 5-aminotetrazolium derivatives] / Levchuk R., Shala M., Rechko Yu., Klapotke T. M., Cudzivo S. // Chemistry of heterocyclic compounds. 2017. Vol. 53, Issue 6/7. P. 697–701.

Flyer vario EL cube. URL: https://www.elementar.de/fileadmin/user_upload/Elementar_Website/Downloads/Flyer/Flyer-vario-EL-cube-EN.pdf

Validation of open: closed arm entries in an elevated plus-maze as a measure of anxiety in the rat / Pellow S., Chopin P., File S. E., Briley M. // Journal of Neuroscience Methods. 1985. Vol. 14, Issue 3. P. 149–167. doi: http://doi.org/10.1016/0165-0270(85)90031-7 

The antioxidant gallic acid induces anxiolytic-, but not antidepressant-like effect, in streptozotocin-induced diabetes / Pereira M. M., de Morais H., dos Santos Silva E., Corso C. R., Adami E. R., Carlos R. M. et. al. // Metabolic Brain Disease. 2018. doi: http://doi.org/10.1007/s11011-018-0264-9 

Derivatives of 1,4-benzodiazepine with selective anxiolytic activity: Pat. No. 2133248 RF. МPK: 7 C07D243/24, A61K31/55 / Seredenin S. B., Blednov Yu. A., Andronati S. A., Pavlovskii V. I., Yavorsky A. S.; zayavitel' i patentoobladatel' Nauchno-issledovatel'skiy institut farmakologii RAMN; Fiziko-himicheskiy institut im. A. V. Bogatskogo Nacional'noy akademii nauk Ukrainy. declareted: 12.07.1995, published: 20.07.1999.

Nootropic and Antihypoxic Properties of Novel Derivatives of 1,2-Dihydro-3H-1,4-Benzodiazepin-2-one / Andronati S. A., Karaseva T. L., Krivenko Y. R., Pavlovsky V. I., Onufrienko O. V., Shandra A. A. // Neurophysiology. 2017. Vol. 49, Issue 6. P. 405–411. doi: http://doi.org/10.1007/s11062-018-9703-9 

Beyer H., Kröger C.-F., Busse G. Über 1.2.4-Triazole, I Die Reaktion von Thiocarbohydrazid und Thiosemicarbazid mit aliphatischen Carbonsäuren und ihren Derivaten // Justus Liebigs Annalen der Chemie. 1960. Vol. 637, Issue 1. P. 135–145. doi: http://doi.org/10.1002/jlac.19606370111 

Hoggarth E. 2-Benzoyldithiocarbazinic acid and related compounds // Journal of the Chemical Society (Resumed). 1952. P. 4811. doi: http://doi.org/10.1039/jr9520004811 

Tautomerism aspect of thione-thiol combined with spectral investigation of some 4-amino-5-methyl-1,2,4-triazole-3-thione Schiff's bases / El Ashry E. S. H., Awad L. F., Soliman S. M., Moaty M. N. A. A., Ghabbour H. A., Barakat A. // Journal of Molecular Structure. 2017. Vol. 1146. P. 432–440. doi: http://doi.org/10.1016/j.molstruc.2017.06.002 

Microwave-Enhanced Reactions of 4-Amino-5-merecapto-1,2,4-triazoles with Benzoyl Chloride and Aromatic Aldehydes / Bai Y., Zhao G., Li C., Zhao S., Shi Z. // Synthetic Communications. 2008. Vol. 38, Issue 19. P. 3311–3319. doi: http://doi.org/10.1080/00397910802136649 

Pruglo Ye. S., Panasenko O. I., Knysh Ye. G. Anxiolytic activity of 4-amino-5-methyl-4H-1,2,4-triazole-3-thion N-derivatives and 2-(4-amino-5-methyl-1,2,4-triazole-3-ylthio) acetic acid salts // Farmacom. 2017. Issue 2. P. 24–29.

Synthesis of some s-triazoles with potential analgesic and antiinflammatory activities / George T., Mehta D. V., Tahilramani R., David J., Talwalker P. K. // Journal of Medicinal Chemistry. 1971. Vol. 14, Issue 4. P. 335–338. doi: http://doi.org/10.1021/jm00286a016 







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