Synthesis and properties of some pyrazole derivatives of 1,2,4-triazole-3-thiol

Nitrogen-containing heterocyclic compounds play an important role in the modern pharmaceutical industry. This is due to their significant biological potential. 1,2,4-Triazole and pyrazole are known pharmacophores that are responsible for the formation of a wide range of activities. The construction of the target molecule using 1,2,4-triazole and pyrazole is also interesting in terms of the availability of starting reagents and the simplicity of chemical transformations. The combination of these heterocycles in one molecule allows increasing its opportunities of participation in various biological processes.

Among the great variety of pharmacologically active molecules, special attention is drawn to the products of the processes of combining individual synthons into a more complex molecule [7][8][9]. For example, pyrazole and 1,2,4-triazole derivatives are well studied and demonstrate a wide range of biological activity. Therefore, a combination of such fragments, which show different mechanisms of interaction with the biological target, within one molecule, is quite interesting and relevant.
Properties (physical, chemical) of the produced organic materials have been examined in compliance with articles of the State Pharmacopoeia. The melting temperature has been defined in open capillary tubes ("MP 100 Melting Point Systems" manufactured by Mettler Toledo). Qualitative and quantitative elemental analysis was carried out with the "Vario EL cube" manufactured by Elementar Analysensysteme GmbH. Infrared spectra were obtained with the ALPHA FT-IR Spectrometer manufactured by Bruker. Nuclear magnetic resonance spectra on Hydrogen nuclei 1 (400 MHz) were recorded using the instrument "Varian Mercury 400 MHz" spectrometer. Tetramethylsilane in dimethylsulfoxide-d 6 solution was used as an internal standard for measuring chemical shifts. Chromatography mass spectra were recorded using the instrument "Agilent 1260 Infinity HPLC" in conjunction with a mass spectrometer "Agilent 6120" (technique of the ionization -electrospray (ESI)).
Molecular docking was performed to obtain structural information on the interaction of the synthesized compounds and the corresponding biological structure [10,11]. In order to solve the indicated problem, models of the necessary biological target were used. The source of the indicated biological models was the Protein Database. Kinases of anaplastic lymphoma (ALK) in the complex of crizotinib, 14-alpha demethylase of lanosterol with ketoconazole and cyclooxygenase-1 (COX-1) with diclofenac were used from the base. AUTODOCK was used to carry out the process of attaching the studied ligands to the proteins under consideration. The energy interaction between the ligand and protein, hydrogen bonds and hydrophobic interaction were used to analyze the docking interaction [12][13][14].

Results
The synthesis of the compounds 7.1-7.10 has been described in Fig. 1. Hydrogen atoms of the thioalkyl fragment generate signals in the strong part of the magnetic field [9]. For example, the Hydrogen signal of the thiomethyl group appears as a singlet at 2.76 ppm (7.1). The lengthening of the alkyl chain first leads to a shift in the signal of the methyl group to a stronger part of the magnetic field (up to S-C 4 H 9 ). Further elongation of the alkyl fragment (S-C 5 ... C 10 ) does not cause significant shifts in the Hydrogen signals of the methyl group. In the mass spectrum, there is a peak of the molecular ion and peaks of fragment ions, which confirm this structure.
It is known about the manifestation of anti-inflammatory activity, which is associated with the combination of triazole and pyrazole fragments within one molecule. In addition, it has been established which aminoacid residues of cyclooxygenases are directly responsible for the formation of hydrogen intermolecular bonds with substances that demonstrate biological activity. Thus, this area of research involving S-alkylderivatives of 5-(5-methylpyrazol-3-yl)-4-ethyl-1,2,4triazole-3-thiol is quite interesting. Cyclooxygenase-1 was chosen as the model enzyme ( Table 2).
The effect of 1,2,4-triazole derivatives on the activity of lanosterol 14-alpha demethylase is a proven fact. It is established that 1 and 2 Nitrogen atoms of 1,2,4-triazole fragment are responsible for the formation of π-π-interaction with the active center of the specified enzyme. Therefore, a docking  study of the effect of synthesized compounds on this enzyme was considered relevant and was carried out ( Table 3).

Discussion
According to the docking results, the synthesized compounds show different levels of binding to the aminoacid residues of anaplastic lymphoma kinase, cyclooxygenase-1 and lanosterol-14α-demethylase.
The transition from thiol to its alkyl derivatives in a number of synthesized compounds leads to an increase in the level of binding to the active centers of anaplastic lymphoma kinase and lanosterol-14α-demethylase.
Docking to cyclooxygenase-1 revealed a decrease in the interaction energy with the specified enzyme of the synthesized alkyl derivatives in comparison with the original thiol. The most relevant for further studies was 3-(5-methylpyrazol-3yl)-5-octylthio-4-ethyl-1,2,4-triazole.
Prospects for further research. According to the research results, it is planned to expand classes of compounds to identify promising biologically active compounds among them.