Synthesis of novel 4H-1,2,4-triazole-3-thiol derivatives with 2-(2,6-dichlorophenylamino)benzyl fragment in molecules and their anti-inflammatory activity

Authors

  • Yu. L. Shepeta Vinnytsya National Pirogov Memorial Medical University,
  • M. I. Lelyukh Danylo Halytsky Lviv National Medical University,
  • B. S. Zimenkovsky Danylo Halytsky Lviv National Medical University,
  • R. B. Lesyk Danylo Halytsky Lviv National Medical University,

DOI:

https://doi.org/10.14739/2409-2932.2016.1.61103

Keywords:

4H-1, 2, 4-triazole, Diclofenac, Alkylation, Anti-Inflammatory Agents

Abstract

Aim. The study of anti-inflammatory activity of novel 4H-1,2,4-triazole-3-thiol derivatives is one of the most priority direction of pharmacological investigation of mentioned heterocyclic system.

Methods and results. Based on the heterocyclization reaction of N-substituted thiosemicarbazides in alkaline medium the synthesis of novel non-condensed derivatives with 4H-1,2,4-triazole and 2-(2,6-dichlorophenylamino)benzyl fragments was carried out. Further chemical modification of synthesized 5-[2-(2,6-dichlorophenylamino)benzyl]-4H-1,2,4-triazole-3-thioles was performed via S-alkylation reactions with N-aryl(thiophene-2-yl)substituted 2-chloroacetamides and 2-chloro-1-(3,5-diaryl-4,5-dihydropyrazol-1-yl)ethanones. Structure of synthesized compounds was confirmed by the elemental analysis and 1H NMR spectral data.

Conclusions. The research of anti-inflammatory activity has been conducted on the carrageenan-induced edema of the rat’s extremities model. The results allow to identify highly active compounds 2-{5-[2-(2,6-dichloro-phenylamino)-benzyl]-4-ethyl-4Н-[1,2,4]triazol-3-ylsulfanyl}-N-(4-chlorophenyl)acetamide (compound 3b) and 2-{5-[2-(2,6-dichloro-phenylamino)-benzyl]-4-ethyl-4Н-[1,2,4]triazol-3-ylsulfanyl}-1-[5-(4-methoxy-phenyl)-3-(naphthalen-2-yl)-4,5-dihydro-pyrazol-1-yl]-ethanone (compound 5c) with evident antiexudative effect comparable with the same effect of diclofenac sodium.

References

Kumar, S. S., & Kavitha, H. P. (2013) Synthesis and biological applications of triazole derivatives – a review. Mini-Reviewers in Organic Chemistry, 5, 40–65.

Franklim, T. N., Freire-de-Lima, L., de Nazareth Sa Diniz, J., Previato, J.O., Castro, R. N., Mendonca-Previato, L., & Freire-de-Lima, M. E. (2013) Design, synthesis and trypanocidal evaluation of novel 1,2,4-triazoles-3-thiones derived from natural piperine. Molecules, 18, 6366–6382. doi: 10.3390/molecules18066366.

Hou, Y.-P., Sun, J., Pang, Z.-H., Lu, P.-C., Li, D.-D., Yan, L., et al. (2011) Synthesis and antitumor activity of 1,2,4-triazoles having 1,4-benzodioxan fragment as a novel class of potent methionine aminopeptidase type II inhibitors. Bioorg. Med. Chem., 19, 5948–5954.

Kumar, H., Javed, S. A., Khan, S. A., & Amir, M. (2008) 1,3,4-Oxadiazole/thiadiazole and 1,2,4-triazole derivatives of biphenyl-4-yloxyacetic acid: Synthesis and preliminary evaluation of biological properties. Eur. J. Med. Chem., 43, 2688–2698. doi: 10.1016/j.ejmech.2008.01.039.

Kucukguzel, S. G., Kucukguzel, I., Tatar, E., Rollas, S., Sahin, F., Gulluce, M., et al. (2007) Synthesis of some novel heterocyclic compounds derived from diflunisal hydrazide as potential anti-infective and anti-inflammatory agents. Eur. J. Med. Chem., 42, 893–901. doi:10.1016/j.ejmech.2006.12.038.

Hashem, A. I., Youssef, A. S. A., Kandeel, K. A., & Abou-Elmagd, W. S. I. (2007) Conversion of some 2(3H)-furanones bearing a pyrazolyl group into other heterocyclic systems with a study of their antiviral activity. Eur. J. Med. Chem., 42, 934–939. doi:10.1016/j.ejmech.2006.12.032.

Zoumpoulakis, P., Camoutsis, Ch., Pairas, G., Sokovic M., Glamoclija J., Potamitis C., & Pitsas A. (2012) Synthesis of novel sulfonamide-1,2,4-triazoles, 1,3,4-thiadiazoles and 1,3,4-oxadiazoles, as potential antibacterial and antifungal agents. Biological evaluation and conformation analysis studies. Bioorg. Med. Chem., 20, 1569–1583. doi: 10.1016/j.bmc.2011.

Kus, C., Ayhan-Kilcigil, G., Ozbey, S., Kaynak, F. B., Kaya, M., Coban, T., & Can-Eke B. (2008) Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class. Bioorg. Med. Chem., 16, 4294–4303. doi: 10.1016/j.bmc.2008.02.077.

Palkar, M. B., Singhai, A. S., Ronad, P. M., Vishwanathswamy, A. H. M., Boreddy, T. S., Veerapur, V. P., et al. (2014) Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents. Bioorg. Med. Chem., 22, 2855–2866. doi: 10.1016/j.bmc.2014.03.043.

Bhandari, S. V., Bothara, K. G., Raut, M. K., Patil, A. A., Sarkate, A. P., & Mokale, V. J. (2008) Design, synthesis and evaluation of anti-inflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4-oxadiazole-2-thiol and Schiff bases of Diclofenac acid as nonulcerogenic derivatives. Bioorg. Med. Chem., 16, 1822–1831. doi: 10.1016/j.bmc.2007.11.014.

Amir, M., & Shikha, K. (2004) Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino)phenyl]acetic acid derivatives. Eur. J. Med. Chem., 39, 535–545. doi: 10.1016/j.ejmech.2004.02.008.

Patel, N. B., & Patel, V. N. (2007) Synthesis and antimicrobial evaluation of new (4-oxothiazolidinyl)-quinazolin-4(3H)-ones of 2-[(2,6-dichlorophenyl)amino]phenylacetic acid. Iranian Journal of Pharmaceutical Research, 6(4), 251–258.

Stefanov, A. V. (2001) Doklinichni doslidzhennia likarskykh zasobiv [Guidelines for the clinical study of drugs]. Kyiv: Avitsenna. [in Ukrainian].

Gacura, V. V. (1974) Metody pervichnogo farmakologicheskogo issledovaniya biologicheski aktivnykh veschestv [Methods primary pharmacological studies of biologically active substances]. Moscow : Medicina. [in Russian]

Liu, J.-J., Zhang, H., Sun, J., Wang, Z.-C., Yang, Y.-S., Li, D.-D., et al. (2012) Synthesis, biological evaluation of novel 4,5-dihydro-2H-pyrazole 2-hydroxyphenyl derivatives as BRAF inhibitors. Bioorg. Med. Chem., 20, 6089–6096. doi: 10.1016/j.bmc.2012.08.020.

El-Sayed, M. A.-A., Abdel-Aziz, N. I., Abdel-Aziz, A. A.-M., El-Azab, A. S., & ElTahir, K. E. H. (2012) Synthesis, biological evaluation and molecular modeling study of pyrazole and pyrazoline derivatives as selective COX-2 inhibitors and anti-inflammatory agents. Part 2. Bioorg. Med. Chem., 20, 3306–3316. doi: 10.1016/j.bmc.2012.03.044.

Bayrak, H., Demirbas, A., Demirbas, N., & Karaoglu, S A. (2010) Cyclization of some carbothioamide derivatives containing antipyrine and triazole moieties and investigation of their antimicrobial activities. Eur. J. Med. Chem., 45, 4726–4732. doi: 10.1016/j.ejmech.2010.07.018.

Ozkay, U. D., Can, O. D., & Kaplancikli, Z. A. (2012) Antinociceptive activities of some triazole and pyrazoline moieties-bearing compounds. Med. Chem. Res., 21, 1056–1061. doi: 10.1007/s00044-011-9619-z.

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How to Cite

1.
Shepeta YL, Lelyukh MI, Zimenkovsky BS, Lesyk RB. Synthesis of novel 4H-1,2,4-triazole-3-thiol derivatives with 2-(2,6-dichlorophenylamino)benzyl fragment in molecules and their anti-inflammatory activity. Current issues in pharmacy and medicine: science and practice [Internet]. 2016Mar.9 [cited 2024Dec.25];(1). Available from: http://pharmed.zsmu.edu.ua/article/view/61103

Issue

No. 1 (2016)

Section

Synthesis of the biologically active compounds

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