Research on the pharmacological potential of 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide

Authors

DOI:

https://doi.org/10.14739/2409-2932.2024.3.311769

Keywords:

4-amino-1,2,4-triazole, design, toxicity, ADME analysis, molecular modeling

Abstract

The heterocyclic system of 1,2,4-triazole and its derivatives is one of the leaders in the development of highly promising biologically active compounds. The peculiarities of the chemical structure of the derivatives of this heterocycle provide a wide range of possibilities for chemical transformations that allow to obtain really effective drugs. The involvement of several substituents in chemical transformations simultaneously, which have the properties of highly reactive centers, additionally creates favorable conditions for the formation of rational ways to create a biologically active compound. Amino-, mercapto- or hydroxogroups often play the role of such groups in chemistry. The use of these groups as substituents of 1,2,4-triazole synthon provides multifaceted opportunities for directed chemical transformation. The ability of such structural fragments to form chemical interactions and bonds with biological targets has an additional positive effect in the sense of their involvement in chemical transformations on the way to the targeted production of a biologically active substance. Thus, the combination of a heterocyclic structure with a highly reactive chemical center is endowed with theoretically sound and practically significant meaning.

The aim of the work is to preliminary determine the potential for creating a biologically active substance with antifungal action based on 1-alkyl derivatives of 3,5-dimethy-l-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide.

Materials and methods. The toxicity of the studied compounds has been predicted using the TEST program (Toxicity Estimation Software Tool), which allowed to determine the predictive level of acute toxicity, ecotoxicity and mutagenicity. The physicochemical and pharmacokinetic parameters have been predicted, and the drug-like properties and availability of the investigated substances have been assessed using the online resource SwissADME. The determination of the most favorable spatial configuration of the ligand relative to the active site of the protein and the assessment of the strength of their interaction have been realized using the computational method of molecular docking. The ligands have been prepared using MarvinSketch 6.3.0, HyperChem 8 and AutoDock Tools-1.5.6 software. The preparation of the model enzyme has been based on the use of Discovery Studio 4.0 and AutoDock Tools-1.5.6. The practical implementation of flexible molecular docking has been carried out using the software tools of the AutoDock/Vina platform.

Results. In the process of step-by-step prescreening of the formed structures of a number of 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide, a number of qualitative and quantitative indicators related to the physicochemical characteristics and pharmacokinetic parameters of the studied substances have been obtained. According to the results of the first stage of research, the group of substances under consideration can be predictively considered low-toxic, but with a high risk of mutagenic properties. The next stage of the work, which involved the analysis of physicochemical parameters, pharmacokinetic parameters, general drug-like properties and bioavailability, allowed us to identify 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide as substances with a rather positive pharmacological profile. The final stage in the form of molecular docking of the structure of the studied compounds to the active site of lanosterol 14α-demethylase allowed us to determine the nature of the chemical interaction and the type of amino acid residues that may be involved in the antifungal properties of the key ligands. The analysis of the docking results allows us to determine the privileged nature of the nonyl substituent at the first Nitrogen atom of the 1,2,4-triazole synthon in the structure of the presented series of compounds for the formation of antifungal properties.

Conclusions. The general prospects for the creation of a biologically active substance with antifungal properties using 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide look quite realistic. Particular attention should be paid to 3,5-dimethyl-1-nonyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide as a substance with significant potential for antifungal properties, which allows us to recommend this compound for further more constructive and extended in vitro and in vivo studies.

Author Biographies

O. I. Panasenko, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

PhD, DSc, Professor, Head of the Department of Toxicological and Inorganic Chemistry

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

PhD, Senior Lecturer of the 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 Toxicological and Inorganic Chemistry

References

Abdelli A, Azzouni S, Plais R, Gaucher A, Efrit ML, Prim D. Recent advances in the chemistry of 1,2,4-triazoles: Synthesis, reactivity and biological activities. Tetrahedron Letters. 2021;86:153518. doi: https://doi.org/10.1016/j.tetlet.2021.153518

Dai J, Tian S, Yang X, Liu Z. Synthesis methods of 1,2,3-/1,2,4-triazoles: A review. Front Chem. 2022;10:891484. doi: https://doi.org/10.3389/fchem.2022.891484

Zarenezhad E, Farjam M, Iraji A. Synthesis and biological activity of pyrimidines-containing hybrids: focusing on pharmacological application. J Mol Struct. 2021:1230. doi: https://doi.org/10.1016/j.molstruc.2020.129833

Slivka MV, Korol NI, Fizer MM. Fused bicyclic 1,2,4-triazoles with one extra sulfur atom: Synthesis, properties, and biological activity. J Heterocyclic Chem. 2020:1-19. doi: https://doi.org/10.1002/jhet.4044

Shcherbyna R, Panasenko O, Polonets O, Nedorezaniuk N, Duchenko M. Synthesis, antimicrobial and antifungal activity of ylidenhydrazides of 2-((4-R-5-R1-4Н-1,2,4-triazol-3-yl)thio)acetaldehydes. Ankara Universitesi Eczacilik Fakultesi Dergisi. 2021;45(3):504-14. doi: https://doi.org/10.33483/jfpau.939418

Samelyuk YG, Kaplaushenko AG. Synthesis of 3-alkylthio(sulfo)-1,2,4-triazoles, containing methoxyphenyl substituents at C5atoms, their antipyretic activity, propensity to adsorption and acute toxicity. Journal of chemical and pharmaceutical research. 2014;6(5):1117-21.

Gotsulya A, Zaika Y, Brytanova T. Synthesis, properties and biological potential some condensed derivatives 1,2,4-triazole. Ankara Universitesi Eczacilik Fakultesi Dergisi. 2022;46(2):308-21. doi: https://doi.org/10.33483/ jfpau.971602

Malani AH, Makwana AH, Makwana HR. A brief review article: Various synthesis and therapeutic importance of 1,2,4-triazole and its derivatives. Mor. J. Chem. 2017;5(1):41-58.

Ogloblina MV, Bushueva IV, Martynyshyn VP, Parchenko VV, Soloviov SO, Gladisheva SA. [Development of industrial production technology with determination of the quality of a soft medicine "Vetmikoderm" for veterinary]. Farmatsevtychnyi zhurnal. 2023;(6):83-93. Ukrainian. doi: https://doi.org/10.32352/0367-3057.6.23.06

Šermukšnytė A, Kantminienė K, Jonuškienė I, Tumosienė I, Petrikaitė V. The effect of 1,2,4-triazole-3-thiol derivatives bearing hydrazone moiety on cancer cell migration and growth of melanoma, breast, and pancreatic cancer spheroids. Pharmaceuticals. 2022;15(8):1026. doi: https://doi.org/10.3390/ph15081026

Grytsai O, Valiashko O, Penco-Campillo M, Dufies M, Hagege A, Demange L, et al. Synthesis and biological evaluation of 3-amino-1,2,4-triazole derivatives as potential anticancer compounds. Bioorg Chem. 2020;104:104271. doi: https://doi.org/10.1016/j.bioorg.2020.104271

Safonov AA. Method of synthesis novel N'-substituted-2-((5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazides. Ankara Universitesi Eczacilik Fakultesi Dergisi. 2020;44(2):242-52. doi: https://doi.org/10.33483/jfpau.580011

Karpenko Y, Hunchak Y, Gutyj B, Hunchak A, Parchenko M, Parchenko V. Advanced research for physico-chemical properties and parameters of toxicity piperazinium 2-((5-(furan-2-yl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)acetate. ScienceRise: Pharmaceutical Science. 2022;2(36):18-25. doi: https://doi.org/10.15587/2519-4852.2022.255848

Gotsulya A. Synthesis and antiradical activity of alkyl derivatives of 5-(5-methyl-1H-pyrazol-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol. Ankara Universitesi Eczacilik Fakultesi Dergisi. 2020;44(2):211-219. doi: https://doi.org/10.33483/jfpau.616116

Fedotov SO, Hotsulia АS. Synthesis and properties of S-derivatives of 4-amino-5-(5-methylpyrazol-3-yl)-1,2,4-triazole-3-thiol Current issues in pharmacy and medicine: science and practice. 2021;14(3):268-274. doi: https://doi.org/10.14739/2409-2932.2021.3.243176

Chekman IS, Nebesna TIu, Symonov PV. In silico: novyi napriam v rozrobtsi farmakolohichnykh ta farmatsevtychnykh vlastyvostei likarskykh zasobiv [In silico: a new direction in the development of pharmacological and pharmaceutical properties of medicinal products]. Klinichna farmatsiia. 2012;16(2):4-14. Ukrainian.

Biovia. Discovery Studio Visualizer, v 19.1.0.18287 [Software]. 2019. Available from: http://www.3dsbiovia.com

ChemAxon. MarvinSketch, Version 6.3.0. [Software]. 2015. Available from: http://www.chemaxon.com

Worldwide Protein Data Bank. (n.d.). Protein Data Bank (PDB) [Database]. Available from: http://www.pdb.org

Additional Files

Published

2024-11-08

How to Cite

1.
Panasenko OI, Brytanova TS, Hotsulia AS. Research on the pharmacological potential of 1-alkyl derivatives of 3,5-dimethyl-4-((4-nitrobenzylidene)amino)-1,2,4-triazolium bromide. Current issues in pharmacy and medicine: science and practice [Internet]. 2024Nov.8 [cited 2024Dec.5];17(3):219-25. Available from: http://pharmed.zsmu.edu.ua/article/view/311769