The synthesis of the substituted 4-alkyl/arylsulfonyl-5-amino-3-alkylthiopyrazoles as promising pharmaceutical agents with the antifungal action

One of the promising directions for development of antifungal agents is the synthesis of new chemical compounds that can be used as active pharmaceutical ingredients to produce highly effective drugs for the treatment of fungal infestations. Aim. To create the combinatorial library of 4-alkyl/arylsulfonyl-5-amino-3-alkylthiopyrazoles derivatives for the total antimicrobial screening to search for new substances with the antifungal activity, and study their spectral properties. Materials and methods. The methods of organic synthesis, instrumental methods of organic compound analysis were used. Results and discussion. The design of the library of small molecules based on the core structure of 5-aminopira-zole has been developed. The useful and effective synthetic scheme for preparing N 1 -subsituted 4-alkyl/arylsulfonyl-5-amino-3-alkylthiopyrazoles and their acylation products has been proposed and approved. This approach consists of cyclization of substituted alkyl/arylsulfoacetonitriles under the action of hydrazine hydrate with further alkylation and acylation of 5-aminopyrazoles obtained. The total yield of the target products is 50-85 %. The structure of all compounds synthesized has been confirmed using elemental analysis, 1 H NMR- and chromato-mass spectrometric methods. Conclusions. The design and the synthetic scheme for obtaining 4-alkyl/arylsulfonyl-5-amino-3-alkiltiopirazoles and products of their chemical modification have been proposed. The compounds synthesized are of certain interest as potential pharmaceutical agents and can be used to develop new antifungal agents.

Ключевые слова: пиразол; комбинаторная библиотека; синтез; фармацевтический агент The global spread of fungal infections trend tends to increase [1][2][3][4][5][6]. This is directly due to the high mobility of the population and because of the increasing proportion of the elderly people in its structure. It can be considered as a constant source of infections. Today more than 400 species of fungi that can cause disease in humans are known. The spectrum of potential fungal pathogens continues to expand, but the dominant clinical value remains Candida and Aspergillus spp [3]. The mortality rate for some forms of Candida infection is 38-75 %, and for invasive aspergillosis this index exceeds 95 % [3]. It should be noted that the effectiveness of the existing pharmaceutical market of antifungal drugs decreases in proportion to the increase in their use due to the spread of resistant clinical strains and is characteristic of all antimicrobial agents.
One of the promising directions for development of antifungal agents is the synthesis of new chemical compounds that can be used as active pharmaceutical ingredients to produce highly effective drugs for the treatment of fungal infestations. Modern developments in the field of chemistry of antifungal agents are new triazoles [7][8][9], echinocandines [9,10], imidazoles [10] and pyrazoles [11][12][13][14][15][16].

Materials and methods
All solvents and reagents were obtained from the commercial sources. Elemental analysis was performed on a Euro EA-3000 apparatus. Melting points were obtained on a Buchi B-520 device. The NMR-spectra were recorded with a Bruker 170 Avance 500 spectrometer at 500 МHz (DMSO-d6); TMS was used as an internal standard; chemical shifts were reported in ppm. LC/MS spectra were recorded with a PE SCIEX API 150EX liquid chromatograph equipped with a UV detector (215 and 254 nm) and using the C18 column (100 × 4 mm).
Elution started with water and ended with acetonitrile/ water (95 : 5, v/v); the linear gradient was used at the flow rate of 0.15 mL/min and the analysis cycle time of 25 min. According to LC/MS data all compounds synthesized have purity > 95 %. The TLC was performed on aluminum plates covered with silica gel (Merck, Kiesgel 60 F-254).

Results and discussion
Recently, we described the synthesis and the antimicrobial activity of some 4-arylsulfonylderivatives of 5-aminopyrazoles and proposed some directions of modification of the pyrazole system for enhancing their action [17]. In this paper the synthetic scheme was proposed. It allows generating structures that combine several fragments characteristic of compounds with the antifungal action. Based on the analysis using the PASS (Prediction of Activity Spectra for Substances) computer program [18] 5-aminopirazole with the substituted sulfonyl-group in position 4 and with branched radicals in position 1 was chosen as a basic structure.
Our approach is in application of the useful and effective synthetic scheme for preparation of N 1 -subsituted 4-alkyl/arylsulfonyl-5-amino-3-alkylthiopyrazoles starting from substituted sulfoacetonitriles shown in Tab. 1. The first stage of the reaction is the cyclization of the  Table 1 Alkylsulfoacetonitriles 1{1-2} and arylsulfoacetonitriles 1{3-6}  One can assume that the compounds synthesized have a broad potential of the pharmacological activity, especially as antifungal agents; and development of methods of the synthesis and the study of pharmacological proper-ties of these compounds are important directions of pharmaceutical and medical chemistry.   СONCLUSIONS The method of the synthesis of series of new substituted 5-amino-3-alkylthiopyrazoles has been developed. They are of great interest for further biological screening in order to find substances with the properties associated with the action on fungal cells among them.