30CHEMISTRY
ACTOPROTECTOR ACTIVITY OF 4-R-(IDENEAMINO)-5-R-4H-1,2,4-TRIAZOLE-3-THIOLS
Asst. Hlazunova T. V., prof. Panasenko O. I., prof. Knysh Ye. H.
Ukraine, Zaporizhzhia, Zaporizhzhia State Medical University
DOI: https://doi.org/10.31435/rsglobal_sr/30112019/6817
ABSTRACT
In this study, actoprotector activity of 1,2,4-triazole derivatives is described. The biological activity of synthetic 4-R-(ideneamino)-5-R-4Н-1,2,4-triazole-3-thiols was analyzed. The forced swim test with a weight load of 10% of the test animal's body weight was applied. According to the obtained results, compounds that contained NH4+ and CuSO4 substituents were among the most active, potency of which was close to that of the reference drug Riboxin. Introduction of propylamine, isopropylamine and piperazine groups into the molecule decreases the actoprotector activity. Compounds containing monoethanolamine, diethylamine, ethylamine, and magnesium sulfate moieties almost did not exhibit actoprotector activity.
Citation: Hlazunova T. V., Panasenko O. I., Knysh Ye. H. (2019) Actoprotector Activity of 4-R-^e^amino^-R^-1,2,4-Triazole-3-Thiols. Science Review. 9(26). doi: 10.31435/rsglobal_sr/30112019/6817
Copyright: © 2019 Hlazunova T. V., Panasenko O. I., Knysh Ye. H. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Fast pace of life people have nowadays often leads to mental and physical exhaustion. A great portion of people, especially those living in cities, have now regularly begun to experience chronic fatigue syndrome, which involves systemic decrease of adaptive defense mechanisms, work productivity, and immunity. This issue is pertinent to athletes who experience fatigue from physical exercises almost every day. The main reason behind the mentioned symptoms is continuous physical and mental loads of high and moderate intensity. In such cases, when rest cannot resolve these issues, physicians may prescribe actoprotectors.
The use of modern medications, which exhibit actoprotector properties, is a promising and effective solution for the enhancement of physical and mental productivity [1]. Various groups of medications are available to address fatigue, ranging from synthetic drugs (Mexidol, Mildronate, Bromantane, Chlodantal, etc.), vitamin products of plant and animal origin (Eleutherococcus, Echinacea purpurea and others), and pill dosage forms (Ecdisten, Immunal) [2]. However, the effect on physical performance becomes apparent only in several weeks after the beginning of the treatment, which creates inconveniences when fatigue must be overcome quickly.
In order to preclude this problem, an emerging class of low-toxic compounds may be used to stimulate productivity, which is actoprotectors [3,4]. Medicinal products of this class do not obstruct external respiratory and cardiovascular functions, stimulate physical productivity, and prevent fatigue. Heterocyclic systems pose great interest in this regard, and low-toxic 1,2,4-triazole derivatives hold a prominent place among them, particularly due to their antiviral, diuretic, anxiolytic, antitumor, and other biological effects [5-7].
Purpose.
Study the actoprotector activity of various 4-R-(ideneamino)-5-R-4#-1,2,4-triazole-3-thiols.
ARTICLE INFO
Received 27 September 2019 Accepted 13 November 2019 Published 30 November 2019
KEYWORDS
actoprotector activity, 1,2,4-triazole derivatives, structure-activity.
Materials and methods. The experiment was conducted on a group of outbred white rats with body weights within 135-319 g. The forced swim test (FST) with a weight load of 10% of the test animal's body weight was applied [8]. Weight load was attached to the tailsets of the animals. Swimming was continued until exhaustion, which was recorded at 10 seconds after the animals were placed in the water. Each rat was placed into a separate water tank with water level of 60 cm. Water temperature was 24-27°C. The studied compounds and reference substance Riboxin were administered abdominally at the dose of 100 mg/kg in 20 minutes before FST [9]. The substances were administered at the dose of 1/10 of LD50 [10]. Swim time was recorded in seconds. For reference, a control group of animals was used, which received normal saline in 20 min prior to the test.
N-N
Table 1.
Compound no. Kat+
1. C4H10NO+
2. HO-CH2CH2-NH3+
3. C4H12N
4. C2H5NH3+
5. NH+
6. K+
7. Na+
8. 1/3Fe3+
9. 1/2Mg2+
10. 1/2Cu2+
11. C5H12N
12. CH3NH3+
13. C5H12NO
14. C12H15N3O
15. C3H10N
16. 1/2Zn2+
17. C3H10N
18. (CH4)2NH+
19. C4H11N2
Results and discussion.
Actoprotector activity of 19 new compounds was studied. It was established that 4-R-(ideneamino)-5-R-4#-1,2,4-triazole-3-thiols exhibit actoprotector effect in range between 34.28% and
12.86% as compared to the reference (Table 2). Table 2.
No. Compound Forced swimming duration, s A%
I. Control (normal saline) 235.43 = 15.588
II. Riboxin 277.00 = 11.745 17.66
III. Kn-56 253.00 = 8.106 7.46
IV. Kn-57 154.71 = 6.335 -34.28
V. Kn-58 258.86 =12.512 9.95
VI. Kn-59 209.29 = 6.778 -11.10
VII. Kn-60 265.71 = 14.138 12.86
VIII. Kn-61 258.00 = 8.861 9.59
IX. Kn-62 261.14 = 6.595 10.92
X. Kn-63 260.14 = 6.638 10.50
XI. Kn-64 155.57 = 6.218 -33.92
XII. Kn-65 265.57 = 9.459 12.80
XIII. Kn-82 242.57 = 11.633 3.03
XIV. Kn-83 260.71 = 12.440 10.74
XV. Kn-92 257.71 = 6.046 9.47
XVI. Kn-93 249.57 = 14.328 6.01
XVII. Kn-94 262.86 = 9.349 11.65
XVIII. Kn-95 243.71 = 11.718 3.52
XIX. Kn-96 262.86 =7.022 11.65
XX. Kn-97 243.71 =11.718 3.52
XXI. Kn-98 263.29 = 6.736 11.83
According to the obtained results, compounds containing NH+ and CuSÜ4 substituents are among the most active, effect of which is close to that of the reference drug Riboxin. Introduction of propylamine, isopropylamine and piperazine groups into the molecule decreases the actoprotector activity.
Introduction of such radicals as NaHCÜ3, FeCb, КНСО3, and such substituents as methylamine and 4-methylmorpholine lowers the actoprotector activity of 2-(((3-mercapto-5-methyl-4H- 1,2,4-triazol-4-yl)imino)methyl)benzoic acid.
Compounds (КП-56, КП-82, КП-93, КП-95, КП-97) have a slightly weaker actoprotector activity. At the same time, substances containing monoethanolamine, diethylamine, ethylamine, and MgSÜ4 moieties almost do not exhibit actoprotector activity.
Conclusions.
Nineteen new synthetic 4-R-(ideneamino)-5-R-4H-1,2,4-triazole-3-thiol derivatives were studied.
It was found that compounds that have NH4+ and CuSÜ4 in its structure are the most potent actoprotectors.
Compounds IV, V, VI, and XI do not exhibit any actoprotector activity.
REFERENCES
1. Ganapolskiy, V. P. (2008). Razrabotka i izucheniye novykh meteo-adaptagenov [Research and development of new meteo-adaptogens]. Dissertation Abstract, HAC RF 14.00.25. S.M. Kirov Military Medical Academy, St.-Petersburg, Russian Federation.
2. Mashkovskiy, M. D. (2002). Lekarstvennyye sredstva [Pharmaceutical products] (Vols. 1-2). S. B. Divov (Ed.). Moscow, Russian Federation: Novaya Volna.
3. Pruhlo, Ye. S., Safonov, A. A., Panasenko, Ü. I., & Knysh, Ye. H. (2013). Aktoprotektorna aktyvnist pokhidnykh N-R-3-alkiltio-5-R1-4H-1,2,4-triazol-4-aminiv [Actoprotector activity of N-R-3-alkylthio-5-R1-4H-1,2,4-triazole-4-amine derivatives]. Current issues in pharmacy and medicine: Science and practice, 3(13), 99-101.
4. Safonov, A. A. (2016). Aktoprotektorna aktyvnist 4-((R-iden)amino)-5-(tiofen-2-ilmetyl)-4H-1,2,4-tryazol-3-tioliv [Actoprotector activity of 4-((R-idene)amino)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-thiol derivatives]. Ukrainian Biopharmaceutical Journal, 2(43), 32-34.
5. Kravchenko, T. V. (2018). The search for new 4-amino-5-methyl-4H-1,2,4-triasole-3-thion derivatives with diuretic activity. Zaporozhye Medical Journal, 20(3), 421-424.
6. Bihdan, Ü. A., Parchenko, V. V., Panasenko, Ü. I., & Knysh, Ye. H. (2016). Farmakolohichni aspekty zastosuvannia furanpokhidnykh 1,2,4-triazol-3-tioliv [Pharmacological aspects of application of 1,2,4-triazole-3-thiol furan derivatives]. Current issues in pharmacy and medicine: Science and practice, 3(22), 98-102.
7. Pruhlo, Ye. S., Hotsulia, A. S., Panasenko, Ü. I., & Knysh, Ye. H. (2013). Anksiolitychna aktyvnist solei 2-((5-((1,3 -dymetyl-2,6-diokso-2,3 -dyhidro- 1N-puryn-7(6N)-il)metyl-4-R-4H-1,2,4-triazol-3 -il)tio)atsetatnykh kyslot [Anxiolytic activity of 2-((5-((1,3-dimethyl-2,6-dioxo-2,3-dihydro-1^-purin-7(6^)-yl)methyl-4-R-4H-1,2,4-triazol-3-yl)thio)acetate salts]. Pharmacology and Drug Toxicology, 3(34), 23-27.
8. Bobkov, Yu. G., Vinogradov, V. I., Katkov, V. F., Losev, S. S., & Smirnov, A. V. (1984). Farmakologicheskaya korrektsiya utomleniya [Pharmacological correction offatigue]. Moscow, Russian Federation: Meditsina.
9. Knysh, Ye. H. (1987). Sintez, fiziko-khimicheskiye i biologicheskiye svoystva N- i S-zameshchennykh 1,2,4-triazola [Synthesis, physical, chemical, and biological properties of N- and S-substituted 1,2,4-triazoles] (Doctoral dissertation). Zaporizhzhia State Medical University, Zaporizhzhia, Ukraine.
10. Stefanov, Ü. B. (Ed.). (2001). Doklinichni doslidzhennia likarskykh zasobiv: Metodychni rekomendatsii [Pre-clinical research of pharmaceuticals: Methodological recommendations]. Kyiv, Ukraine: Avitsena.
