Pharmacological potential of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides

Authors

DOI:

https://doi.org/10.14739/2409-2932.2024.2.302351

Keywords:

1,2,4-triazole, properties, in silico studies, biological potential

Abstract

The discovery of new 1,2,4-triazole derivatives offers significant potential for the development of innovative medications. Researchers often favor derivatives of this heterocyclic system due to their ability to create chemical structures with desired pharmacokinetic and pharmacodynamic properties, allowing for targeted effects on specific biological targets. Importantly, biologically active compounds containing triazole have demonstrated relatively low toxicity and minimal risks of mutagenicity. The synergistic combination of these characteristics provides favorable conditions for the development of complex therapeutic effects, ultimately leading to the creation of novel biologically active substances and offering new avenues for the effective treatment of various diseases.

Indeed, the utilization of a diverse array of chemical transformations and functionalizations is crucial for obtaining bioactive molecules with desired properties. In this context, 1,2,4-triazole and its derivatives offer a platform for executing a comprehensive range of chemical transformations, thereby enabling the development of compounds with enhanced pharmacokinetic and pharmacodynamic parameters.

The aim of the study was to preliminarily assess the possibility of creating a biologically active substance based on 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-R-1,2,4-triazole halides.

Materials and methods. In silico analysis was used to assess the safety and potential toxicity of the presented compounds, which was implemented using the T.E.S.T. software developed by the US Environmental Protection Agency. SwissADME is an online resource as an effective tool for studying the physicochemical properties and pharmacokinetic parameters of the compounds proposed for study. A molecular docking method that uses a variety of computational algorithms to predict and analyze interactions, including determining the presence of possible binding sites, estimating binding energies, and the spatial arrangement of molecules. The ligand models were created using MarvinSketch 6.3.0, Hyper Chem 8, and AutoDockTools-1.5.6. Discovery Studio 4.0 and AutoDockTools-1.5.6 have been used to prepare the enzymes for analysis. For direct molecular docking, Vina software has been used, which allows predicting and evaluating the interaction between the ligand molecule and the three-dimensional structure of the target protein, taking into account their energy and spatial compatibility.

Results. A virtual set of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides was prescreened, which are potential candidates for the further synthesis of biologically active compounds. The general level of toxicity and harmlessness was determined at the predictive level. The key physicochemical characteristics of the molecules have been determined and the general pharmacokinetic parameters have been identified, which allows for a better understanding of their interaction and behavior in the body. The active sites of the model enzymes were analyzed using Vina software, which contributes to a deeper understanding of the interaction of enzymes with their substrates.

According to the results of the study, an increased probability of the formation of anti-inflammatory and anticancer properties occurs in 1-alkyl derivatives of 3,5-dimethyl-4-(3-((5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides with an odd number of Сarbon atoms. Instead, the highest affinity for lanosterol 14α-demethylase has been demonstrated in the studied derivatives with octyl and nonyl substituents, which shows a certain probability of antifungal activity.

Conclusions. The prognosis for the creation of a biologically active substance using 1-alkyl derivatives of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1,2,4-triazolium halides is quite favorable.

Author Biographies

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

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

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

References

Elmongy EI, Alanazi WS, Aldawsari AI, Alfaouri AA, Binsuwaidan R. Antimicrobial Evaluation of Sulfonamides after Coupling with Thienopyrimidine Coplanar Structure. Pharmaceuticals (Basel). 2024;17(2):188. doi: https://doi.org/10.3390/ph17020188

Afsarian MH, Farjam M, Zarenezhad E, Behrouz S, Rad MN. Synthesis, Antifungal Evaluation and Molecular Docking Studies of Some Tetrazole Derivatives. Acta Chim Slov. 2019;66(4):874-87.

Shcherbyna R, Panasenko O, Polonets O, Nedorezanıuk 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. Journal of Faculty of Pharmacy of Ankara University. 2021;45(3):504-14. doi: https://doi.org/10.33483/jfpau.939418

Samelyuk Y, Kaplaushenko A. Synthesis of 3-alkylthio(sulfo)-1,2,4-triazoles, Containing methoxyphenyl substituents at c5atoms, Their antipyretic activity, Propensity to adsorption and acute toxicity. J Chem Pharm Res. 2014:6(5):1117-21.

Safonov A. Method of synthesis novel N'-substituted 2-((5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazides. Journal of Faculty of Pharmacy of Ankara University. 2020;44(2):242-52. doi: https://doi.org/10.33483/jfpau.580011

Gotsulya A, Zazharskyi V, Parchenko V, Davydenko P, Kulishenko O, Brytanova T. N’-(2-(5-((theophylline-7-yl)methyl)-4-ethyl-1,2,4-triazole-3-ylthio)-acetyl)isonicotinohydrazide as antitubercular agents. Hacettepe University Journal of the Faculty of Pharmacy. 2022;42(3):149-55. doi: https://doi.org/10.52794/hujpharm.1011368

Demchenko S, Lesyk R, Yadlovskyi O, Holota S, Yarmoluk S, Tsyhankov S, et al. Fused triazole-azepine hybrids as potential non-steroidal antiinflammatory agents. Scientia pharmaceutica. 2023;91(2):26-6. doi: https://doi.org/10.3390/scipharm91020026

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):18-25. doi: https://doi.org/10.15587/2519-4852.2022.255848

Abdellatif KR, Abdelall EK, Elshemy HA, Philoppes JN, Hassanein EH, Kahk NM. Optimization of pyrazole-based compounds with 1,2,4-triazole-3-thiol moiety as selective COX-2 inhibitors cardioprotective drug candidates: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory, ulcerogenicity, cardiovascular evaluation, and molecular modeling studies. Bioorg Chem. 2021;114:105122. doi: https://doi.org/10.1016/j.bioorg.2021.105122

Fadaly WA, Elshaier YA, Hassanein EH, Abdellatif KR. New 1,2,4-triazole/pyrazole hybrids linked to oxime moiety as nitric oxide donor celecoxib analogs: Synthesis, cyclooxygenase inhibition anti-inflammatory, ulcerogenicity, anti-proliferative activities, apoptosis, molecular modeling and nitric oxide release studies. Bioorg Chem. 2020;98:103752. doi: https://doi.org/10.1016/j.bioorg.2020.103752

Bian M, Ma QQ, Wu Y, Du HH, Guo-Hua G. Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review. J Enzyme Inhib Med Chem. 2021;36(1):2139-59. doi: https://doi.org/10.1080/14756366.2021.1984903

Azim T, Wasim M, Akhtar MS, Akram I. An in vivo evaluation of anti-inflammatory, analgesic and anti-pyretic activities of newly synthesized 1, 2, 4 Triazole derivatives. BMC Complement Med Ther. 2021;21(1):304. doi: https://doi.org/10.1186/s12906-021-03485-x

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):268-74. doi: https://doi.org/10.14739/2409-2932.2021.3.243176

Fedotov SO, Hotsulia AS. Synthesis and properties of 6-(2,6-dichlorophenyl)-3- (3-methyl-1H-pyrazol-5-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine-7-carboxylic acid and its salts. Current issues in pharmacy and medicine: science and practice. 2023;16(2):121-9. doi: https://doi.org/10.14739/2409-2932.2023.2.279460

Chekman IS, Nebesna TY, 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 medicines]. Klinichna farmatsiia. 2012;16(2):4-14. Ukrainian.

Brytanova TS. [Synthesis, chemical and biological properties of derivatives of 4-benzylidenamino- and 4-(furan-2-ylmethylenamino)-1-R-4H-1,2,4-triazolium halogenides] [dissertation on the Internet]. Zaporizhzhia: Zaporozhye State Medical University; 2012 [cited 2024 Apr 11]. Available from: https://nrat.ukrintei.ua/en/searchdoc/0412U003044/

US EPA O. Toxicity Estimation Software Tool (TEST) [Internet]. www.epa.gov. 2015. Available from: https://www.epa.gov/comptox-tools/toxicity-estimation-software-tool-test

Biovia [Internet]. Dassault Systèmes. 2023 [cited 2024 Apr 11]. Available from: http://www.3dsbiovia.com

ChemAxon - Software Solutions and Services for Chemistry & Biology [Internet]. chemaxon.com. Available from: http://www.chemaxon.com

Protein Data Bank [Internet]; [сited 2024 Apr 11]. Available from: https://www.wwpdb.org/

Published

2024-06-14

How to Cite

1.
Hotsulia AS, Panasenko OI, Brytanova TS. Pharmacological potential of 3,5-dimethyl-4-(3-(5-nitrofuran-2-yl)allylidenamino)-1-alkyl-1,2,4-triazolium bromides. Current issues in pharmacy and medicine: science and practice [Internet]. 2024Jun.14 [cited 2024Jul.21];17(2):115-21. Available from: http://pharmed.zsmu.edu.ua/article/view/302351