Синтез, будова та властивості N-R-2-(5-(5-метил-1H-піразол-3-іл)-4-феніл-4H-1,2,4-тріазол-3-ілтіо)ацетамідів

A. S. Hotsulia; S. O. Fedotov

doi:10.14739/2409-2932.2019.1.158913

Authors

A. S. Hotsulia Zaporizhzhіa State Medical University, Ukraine,
S. O. Fedotov Zaporizhzhіa State Medical University, Ukraine,

DOI:

https://doi.org/10.14739/2409-2932.2019.1.158913

Keywords:

1, 2, 4-triazole, pyrazole, physical-chemical properties, molecular docking.

Abstract

Heterocyclic compounds remain the most promising group of compounds, through which the new drugs with characteristic list of properties are successfully created. Examples of this systems are 1,2,4-triazole and pyrazole. The presence in one molecule structure of fragments of two different azaheterocycles is synthetically interesting and allows increasing the probability to obtain biologically active substance with a wide spectrum of action.The aim of the work was to optimize the synthesis conditions and investigate the properties of N-R-2-(5-(5-methyl-1H-pyrazole-3-yl)-4-phenyl-4H-1,2,4-triazole-3-ylthio)acetamides in case of change of chemical process conditions.Methods and results. Ethyl 5-methyl-1H-pyrazole-3-carboxylate, which was obtained by known techniques using acetone, diethyl oxalate, sodium methoxide, followed by hydrazine hydrate in equivalent amount, was used as the key starting reagent. The resulting ethyl 5-methyl-1H-pyrazole-3-carboxylate was used to carry out hydrazinolysis reactions and nucleophilic addition of phenyl isothiocyanate with subsequent alkaline heterocyclicization. The synthesized 5-(5-methyl-1H-pyrazol-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiole was used in alkylation reactions with promising reagents for the design of pharmacophoric fragments. The products of such reaction are N-R-2-(5-(5-methyl-1H-pyrazole-3-yl)-4-phenyl-4H-1,2,4-triazole-3-ylthio)acetamides. The structure of the resulting compounds was confirmed by elemental analysis, ¹H NMR spectroscopy, IR spectrophotometry. The individuality of the substances was determined by thin-layer chromatography and chromatographic mass spectrometry. For synthesized compounds, preliminary screening was performed using the PASS On-line^® software and molecular docking.Conclusions. N-R-2-5-(5-methyl-1H-pyrazole-3-yl)-4-phenyl-4H-1,2,4-triazole-3-ylthio)acetamides are obtained with high yields and purity, their properties are investigated.

References

El-Sherief, H. A. M., Youssif, B. G. M., Bukhari, S. N. A., Abdel-Aziz, M., & Abdel-Rahman, H. M. (2018). Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors. European Journal of Medicinal Chemistry, 156, 774–789. doi: 10.1016/j.ejmech.2018.07.024.

Sayed, S. M., Khalil, M. A., & Raslan, M. A.-E. (2014). Synthesis of pyrazole, 1,3-dithiolan and thiophene derivatives pendant to thiazolo[2,3-c]-1,2,4-triazole moiety. European Journal of Chemistry, 5(2), 356–362. doi: 10.5155/eurjchem.5.2.356-362.1022.

Lin, K., Chile, L.-E., Zhen, S. C., Boyd, P. D. W., Ware, D. C., & Brothers, P. J. (2014). Pyrrole pincers containing imidazole, pyrazole and 1,2,4-triazole groups. Inorganica Chimica Acta, 422, 95–101. doi: 10.1016/j.ica.2014.07.022.

Kaur, R., Dwivedi, A. R., Kumar, B., & Kumar, V. (2016). Recent Developments on 1,2,4-Triazole Nucleus in Anticancer Compounds: A Review. Anti-Cancer Agents in Medicinal Chemistry, 16(4), 465–489. doi: 10.2174/1871520615666150819121106.

Karrouchi, K., Chemlal, L., Taoufik, J., Cherrah, Y., Radi, S., El Abbes Faouzi, M., & Ansar, M. (2016). Synthesis, antioxidant and analgesic activities of Schiff bases of 4-amino-1,2,4-triazole derivatives containing a pyrazole moiety. Annales Pharmaceutiques Françaises, 74(6), 431–438. doi: 10.1016/j.pharma.2016.03.005.

Li, Y.-S., Tian, H., Zhao, D.-S., Hu, D.-K., Liu, X.-Y., Jin, H.-W., et al. (2016). Synthesis and bioactivity of pyrazole and triazole derivatives as potential PDE4 inhibitors. Bioorganic & Medicinal Chemistry Letters, 26(15), 3632–3635. doi: 10.1016/j.bmcl.2016.06.002.

Wang, B.-L., Zhang, L.-Y., Zhan, Y.-Z., Zhang, Y., Zhang, X., Wang, L.-Z., & Li, Z.-M. (2016). Synthesis and biological activities of novel 1,2,4-triazole thiones and bis(1,2,4-triazole thiones) containing phenylpyrazole and piperazine moieties. Journal of Fluorine Chemistry, 184, 36–44. doi: 10.1016/j.jfluchem.2016.02.004.

Tarikoğulları, A. H., Çizmecioğlu, M. M., Saylam, M., Parlar, S., Alptüzün, V., & Soyer, Z. (2016). Synthesis and cholinesterase inhibitory activity of some phenylacetamide derivatives bearing 1H-pyrazole or 1H-1,2,4-triazole. Marmara Pharmaceutical Journal, 20, 21–27. doi: 10.12991/mpj.2016202105828.

Karrouchi, K., Radi, S., Ramli, Y., Taoufik, J., Mabkhot, Y. N., Al-Aizari, F. A., & Ansar, M. (2018). Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review. Molecules, 23(1), 431–438. doi: 10.3390/molecules23010134.

Pillai, R. R., Karrouchi, K., Fettach, S., Armaković, S., Armaković, S. J., Brik, Y., et al. (2019). Synthesis, spectroscopic characterization, reactive properties by DFT calculations, molecular dynamics simulations and biological evaluation of Schiff bases tethered 1,2,4-triazole and pyrazole rings. Journal of Molecular Structure, 1177, 47–54. doi: 10.1016/j.molstruc.2018.09.037.