Synthesis, molecular docking, and ADME analysis of a series of 4-amino-3,5-dimethyl-1,2,4-triazole derivatives

Authors

DOI:

https://doi.org/10.14739/2409-2932.2023.2.281039

Keywords:

1,2,4-triazole, synthesis, molecular docking, ADME analysis

Abstract

The heterocyclic system of 1,2,4-triazole enables the successful creation of promising biologically active compounds. By creating a range of derivatives based on 4-amino-3,5-dimethyl-1,2,4-triazole, the spectrum of potential biologically active compounds can be expanded.

The aim of the work was the synthesis and in silico justification of the prospects for the search for biologically active compounds among 4-amino-3,5-dimethyl-1,2,4-triazole derivatives.

Materials and methods. The work uses modern methods for synthesizing organic compounds, followed by confirmation of their individuality and structure through the analysis of physical-chemical parameters and spectroscopic techniques such as 1H NMR, IR spectroscopy, elemental analysis, and chromatography-mass spectrometry. To assess the similarity of the synthesized compounds to medicinal products, the SwissADME online tool was employed. The probability of impact on a number of enzyme systems (cyclooxygenase-2, lanosterol 14α-demethylase, anaplastic lymphoma kinase) was estimated using molecular docking.

Results. A series of newly synthesized derivatives of 4-amino-3,5-dimethyl-1,2,4-triazole was obtained, and the synthesis conditions were optimized and their structures were confirmed. It was determined that there is a high probability of influencing lanosterol 14α-demethylase, highlighting the significance of further research on the antifungal activity of the synthesized compounds. Additionally, the potential influence on the activity of cyclooxygenase-2 and anaplastic lymphoma kinase was discovered. However, the probability of exhibiting the corresponding activities, namely anti-inflammatory and anti-cancer, is low. Physical indicators, parameters of pharmacokinetics, and drug-likeness are important, which determines the prospects of creating biologically active substances based on the synthesized series of compounds.

Conclusions. A series of 4-((R-iden)amino)-3,5-dimethyl-1,2,4-triazoles were synthesized, and their general physical-chemical properties were determined. The overall potential for creating innovative biological products based on these compounds was assessed using in silico methods for predicting the activity of substances.

Author Biographies

L. I. Kucherenko, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, DSc, Professor, Head of the Department of Pharmaceutical, Organic and Bioorganic Chemistry

T. S. Brytanova, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, Teaching Assistant, Department of Pharmaceutical, Organic and Bioorganic Chemistry

A. S. Hotsulia, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, DSc, Associate Professor of the Department of Natural Sciences for Foreign Students and Toxicological Chemistry

References

Singhal, N., Sharma, P. K., Dudhe, R., & Kumar, N. (2011). Recent advancement of triazole derivatives and their biological significance. Journal of Chemical and Pharmaceutical Research, 3(2), 126-133.

Zhou, C.-H., & Wang, Y. (2012). Recent Researches in Triazole Compounds as Medicinal Drugs. Current Medicinal Chemistry, 19(2), 239-280. https://doi.org/10.2174/092986712803414213

Wajda-Hermanowicz, K., Pieniazczak, D., Zatajska, A., Wróbel, R., Drabent, K., & Ciunik, Z. (2015). A study on the condensation reaction of 4-amino-3,5-dimethyl-1,2,4-triazole with benzaldehydes: Structure and spectroscopic properties of some new stable hemiaminals. Molecules, 20(9), 17109-17131. https://doi.org/10.3390/molecules200917109

Jaman, Z., Karim, M. R., Dumenyo, K., & Mirza, A. H. (2014). Antibacterial Activities of New Schiff Bases and Intermediate Silyl Compounds Synthesized from 5-Substituted-1,10-phenanthroline- 2,9-dialdehyde. Advances in Microbiology, 04(15), 1140-1153. https://doi.org/10.4236/aim.2014.415124

Aggarwal, R., & Sumran, G. (2020). An insight on medicinal attributes of 1,2,4-triazoles. European Journal of Medicinal Chemistry, 205. https://doi.org/10.1016/j.ejmech.2020.112652

Hu, G., Wang, G., Duan, N., Wen, X., Cao, T., Xie, S., & Huang, W. (2012). Design, synthesis and antitumor activities of fluoroquinolone C-3 heterocycles (IV): s-triazole Schiff–Mannich bases derived from ofloxacin. Acta Pharmaceutica Sinica B, 2(3), 312-317. https://doi.org/10.1016/j.apsb.2011.11.003

Cheng, L., Zhang, W. X., Ye, B. H., Lin, J. B., & Chen, X. M. (2007). In situ solvothermal generation of 1,2,4-triazolates and related compounds from organonitrile and hydrazine hydrate: A mechanism study. Inorganic Chemistry, 46(4), 1135-1143. https://doi.org/10.1021/ic061303i

Wu, B. D., Bi, Y. G., Zhou, M. R., Zhang, T. L., Yang, L., Zhou, Z. N., & Zhang, J. G. (2014). Stable high-nitrogen energetic trinuclear compounds based on 4-amino-3, 5-dimethyl-1, 2, 4-triazole: Synthesis, structures, thermal and explosive properties. Zeitschrift Fur Anorganische Und Allgemeine Chemie, 640(7), 1467-1473. https://doi.org/10.1002/zaac.201300446

Karpun, Y., Fedotov, S., & Khilkovets, A. An in silico investigation of 1,2,4-triazole derivatives as potential antioxidant agents using molecular docking, MD simulations, MM-PBSA free energy calculations and ADME predictions. Pharmacia, 2023, 70(1), 139-153. https://doi.org/10.3897/pharmacia.70.e90783

Fedotov, S., Gotsulya, A., Zaika, Ye., & Brytanova, T. (2023). Design, synthesis and molecular docking of some derivatives of 9-methylpyrazolo[1,5-d][1,2,4]triazolo [3,4-f][1,2,4]triazine-3-thiol. Journal of Faculty of Pharmacy of Ankara University, 47(2), 336-348. https://doi.org/10.33483/jfpau.1180794

Bocci, G., Carosati, E., Vayer, P., Arrault, A., Lozano, S., & Cruciani, G. (2017). ADME-Space: A new tool for medicinal chemists to explore ADME properties. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-06692-0

Swiss Institute of Bioinformatics. (2023). SwissADME. http://swissadme.ch/index.php#

Published

2023-07-03

How to Cite

1.
Kucherenko LI, Brytanova TS, Hotsulia AS. Synthesis, molecular docking, and ADME analysis of a series of 4-amino-3,5-dimethyl-1,2,4-triazole derivatives. Current issues in pharmacy and medicine: science and practice [Internet]. 2023Jul.3 [cited 2024Apr.14];16(2):147-53. Available from: http://pharmed.zsmu.edu.ua/article/view/281039

Issue

Section

Original research