Synthesis and analgesic activity of new pyrazole-containing derivatives of 1,2,4-triazole-3-thiol
Authors: Fedotov S. O. , Hotsulia A. S. , Karpenko Yu. V. 
Published: December 2023

Pain represents a primary symptom of numerous diseases and conditions, affecting millions of people worldwide. Effective analgesic medications can alleviate or eliminate pain, thereby enhancing patients’ quality of life and assisting them in resuming normal physical and social activities. However, several existing analgesics may carry unwanted side effects, such as ulcers, blood clotting issues, drowsiness, and more. The development of new analgesics is focused on creating drugs that are both effective and associated with fewer adverse effects. Considering the continuous rise in the number of patients dealing with neurological, oncological, and other conditions accompanied by chronic pain, there is a growing demand for innovative methods of treatment and pain management. The combination of two different heterocyclic fragments within one molecule makes it possible to use the possibilities of influencing such a molecule on various mechanisms of occurrence and development of various pathological conditions, including those accompanied by pain. Chemical modifications of pyrazole and 1,2,4-triazole structures, involving their incorporation into a single molecule, have the potential, as suggested by in silico predictions, to yield biologically active compounds with analgesic properties.
The aim of this work was to determine the optimal conditions for the chemical transformation and properties of 4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazole-3-thiol, 4-amino-5-(3-(3-fluorophenyl)pyrazol-5-yl)-1,2,4-triazole-3-thiol and their derivatives for the preparation of bioactive systems with analgesic activity.
Materials and methods. The creation of a target series of compounds was implemented by consistently using well-known methods of organic synthesis. 4-Amino-5-(3-methylpyrazole-5-yl)-1,2,4-triazole-3-thiol and 4-amino-5-(3-(3-fluorophenyl)pyrazole-5-yl)-1,2,4-triazole-3-thiol were resynthesized as starting materials using acetone or 1-(3-fluorophenyl)ethane-1-one, diethyloxalate, and sodium methylate using step-by-step hydrazinolysis and carbon disulfide involvement in an alkaline medium. Further targeted functionalization involved the introduction of a 2,6-dichlorophenyl substitute, alkane acid residues, and esters based on them into the structure of the target compounds. The structure of all synthesized substances was determined by IR spectrophotometry, 1H NMR spectroscopy, and elemental analysis. The individuality of the compounds was confirmed by high-performance liquid chromatography-mass spectrometry. The analgesic properties were studied on two models: the “acetic acid-induced writhing test” and a formalin model of pain inflammation. Pharmacokinetic parameters were predictably calculated using the SwissADME online platform.
Results. Based on the results of the synthetic part of the work, the structure of 4-amino-5-(3-methylpyrazole-5-yl)-1,2,4-triazole-3-thiol and 4-amino-5-(3-(3-fluorophenyl)pyrazole-5-yl)-1,2,4-triazole-3-thiol, as well as their derivatives, was successfully recreated. The presence of a beneficial effect of 2,6-dichlorophenyl substitute, as well as fragments of saturated carboxylic acids and their esters on the formation of antinociceptive activity has been proven. The quantitative indicators of pharmacokinetic parameters, as determined during ADME analysis, fall within acceptable ranges in nearly all instances.
Conclusions. The optimal conditions for the synthesis and structural modification of 4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazole-3-thiol, 4-amino-5-(3-(3-fluorophenyl)pyrazol-5-yl)-1,2,4-triazole-3-thiol were established, which allowed the preparation of 2-((4-amino-5-(3-methylpyrazol-5-yl)-1,2,4-triazol-3-yl)thio)alkanoic acids and their esters, as well as [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine systems. It has been shown that the combination of pyrazole derivatives of 1,2,4-triazol-3-thiol with 2,6-dichlorophenyl substituent and fragments of saturated carboxylic acids and their esters creates conditions for the formation of compounds with antinociceptive activity, which was confirmed in vivo by experimental data acetic acid-induced writhing test and formalin inflammation model.