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Derivatives of 1,2,4-triazole are inherent in various types of biological activity. They can be used as pesticide and medicinal drugs (anticonvulsants, analgetics, antitumor and antibacterial). In this regard the search of new methods of synthesis and investigation of biological activity of 2-(4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-ylthio)acetate acids and their salts is relevant nowadays. With the aim of finding the new biologically active compounds 2-(4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-ylthio)acetate acids and their salts are synthesized, where R is methyl, ethyl, phenyl. The interaction of 4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-thions with monochloracetate acid in the medium of i-propyl alcohol in the presence of an equivalent amount of alkali the corresponding 2-(4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4 triazole-3-ylthio)acetate acids are obtained on the basis of which the corresponding salts of morpholine, dimethylamine, monoethanolamine, pteridine, ZnSO4 , CuSO4, NaOH and KOH are obtained and the structure of the received compounds was confirmed on the basis of the data of elemental, IR-, 1H-NMR-spectroscopy. The synthesis of 2-(4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-ylthio) acetate acids and their salts was conducted. With the help of modern physico-chemical methods: elemental analysis, IR, 1H-NMR-spectroscopy the structure of synthesized compounds, and their individuality by HPLC-MS is proved. In the IR spectrum of the compound 2-(4-phenyl-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-ylthio)acetate acid Ic available band fluctuations groups characteristic for the nucleus of 1,2,4-triazole: NH– in the range of 3 400–3 100 cm-1,–C=N– – 1 690–1 620 cm-1. Also present band fluctuations groups –C–S– at 691 cm-1. Available band fluctuations characteristic of the group –CH2 within 1496.59 cm-1 and group –COO-H– – 1722.70 cm-1. This suggests the possibility to further study the biological action of the synthesized compounds.

The aim of this work was the synthesis of bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkanes using available reagents and study of their properties. Matherial and methods. 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-thiol was used as an intermediate compound, obtained from methyl 2-(thiophen-2-yl)acetate. Its synthesis has been described in previous studies. During the bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkane moiety formation stage, dibromoalkanes (dibromomethane, dibromopropane, dibromobuthane) were used as secondary reagents. The reaction was conducted in propan-2-ol. The presence of reaction products has been confirmed applying spectral methods. Synthesis of bis((4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)alkanes 0.01 M of the correspondent alkyl halide is added to the corresponding 3-(3-R-1,2,4-triazol-5-thiomethyl)-1,2,4-triazol-5-thione (0.01 M) in mixture of 0.01 mole NaОН and 30 mL of ethanol or propan-1-ol, and the mixture is boiled until the neutralization (during 3 hours reflux). The mixture is filtered, solvent is evaporated. White crystalline matter, practically insoluble in water, soluble in organic solvents. Compounds were purified by recrystallization from dimethylformamide-water mixture (1:1). Results. Distinction of compounds was confirmed by chromatography-mass-spectrometry. 1H NMR spectra of the obtained compounds were characterized by number of signals. The protons of alkylsulfide fragment resonate in a weak field appearing as multiplets at 3.12–3.07 ppm and 2.25–2.10 ppm. The protons of methyl group, which bond the heteroaromatic fragments together, resonate as a singlet at 3.92–3.87 ppm. Aromatic protons of thiophene fragments appear as multiplets at 6.95–6.78 and 6.99–7.20 ppm. The protons of methyl fragment of N-alkyl substituent appear as a multiplet at 4.21–3.98 ppm, protons of methyl fragment resonate as a triplet at 1.52–1.57 ppm. IR spectra of the studied compounds showed presence of C-S fragment, which appears as a band of molecular stretching at 693 cm-1. Stretching vibrations of С-H fragment of thiophene ring is observed at 715–693 cm-1. The CH2 fragment appears as strong stretching (at 2935–2905 cm-1 and 2865–2855 cm-1) and moderate bending vibrations (at 1493–1460 cm-1). Also recommended for “polymethylene fragment” are characteristic deformation vibrations at 730–720 cm-1. Symmetrical and asymmetrical bending at 1385–1380 and 1470–1465 cm-1characterize the presence of СН3 group. Preliminary screening of acute toxicity and biological activity parameters has been carried out. Conclusions. Nine compounds were obtained; their structures were confirmed.The characteristics of the synthesized compounds were assessed with computer processing using PASS online tool. The most promising compounds were selected for in vitro research. It was clarified during the analysis of results that the obtained compounds may exhibit various types of biological activities. The most probable effect predicted for the nine studied compounds is antimicrobial activity. 1,2,4-triazole, bis-derivatives, synthesis, IR spectroscopy, 1Н NMR spectroscopy, PASS-screening

It should be noted, that the clinical and therapeutic effect of diuretic drugs is not necessarily associated with an increase diuresis. So, for example, diuretics are also prescribed as a means of dehydration emergency therapy for pulmonary edema, brain, in the integrated therapy of patients with arterial hypertension, with glaucoma, epilepsy, as well as for induction of forced diuresis in poisoning. Therefore, the search for new diuretic agents among heterocyclic systems can solve the problem of treating a complex of diseases of different genesis. The aim of this work was to study the diuretic activity of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole derivatives. Materials and methods. The method of E. B. Berchin was used to establish the influence of synthesized compounds on the excretory function of the kidneys. All compounds for this research have been synthesized at the Toxicological and Inorganic Chemistry Department of ZSMU. Results and discussion. Diuretic activity of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol derivatives was investigated. Some regularities between “structure – activity” were established: the replacement of the phenyl radical in the 4-phenyl-5-(thiophen-2- ylmethyl)-4H-1,2,4-triazole-3-thiol molecule with ethyl or methyl leads to a slight increase in diuretic effect. The introduction of alkyl radical to 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triasole-3-thiol molecule results in diuretic effect increase. The introduction of 2-chloro-6- fluorobenzyl, 4-hydroxybenzyl and 3,5-dimethoxybenzyl radical to N’-R1 -iden-2-((4-methyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl) thio)acetohydrazide molecule also results in diuretic activity increase. Replacement of 3,4-difluorobenzyl radical with 4-fluorobenzyl, 2-bromobenzyl, 2-hydroxybenzyl to N’-R1 -iden-2-((4-phenyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide molecule results in diuretic activity decrease. Conclusions. The diuretic activity of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazoles derivatives was established by the method of Ye. B. Berchin. The derivatives of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazoles exhibit both diuretic and antidiuretic effects. Some relationship between “structure – activity” was established. The most active compound was 3-(heptylthio)-4-methyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole.

The urgency of the search for new biologically active compounds among the 1,2,4-triasole derivatives is beyond doubt. The promise of this direction has been confirmed by many publications by both domestic and foreign scientists. It is known that various derivatives of 1,2,4-triazole are low-toxic or practically non-toxic compounds, while possessing a wide range of biological effects. As we know, one of the main priorities of the introduction of new substances is a minor toxicity. Therefore, purposeful synthesis of low-toxic compounds and focused study of acute toxicity are the priority tasks of pharmacological research. The aim of the work was to study the acute toxicity of the first synthesized S-derivatives of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazoles. Materials and methods. An express method of V. B. Prozorovsky was selected for the study of acute toxicity. The basis of this method is the use of test substances in doses located on a logarithmic scale with an interval of 0.1, and all possible reliable LD50 results and their errors are calculated by pre-program of the probit analysis. Results. As a result of the studies, it was found that the acute toxicity of the synthesized compounds is within the limits of 193–770 mg/kg. According to K. K. Sidorov classification they are low-toxic or practically non-toxic compounds. The most toxic compound among thioles is 4-methyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol – 304 ± 65 mg/kg. The acute toxicity of N'-R1-iden-2-((4-methyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetohydrazides are within the range of 193–770 mg/kg. Conclusions. The acute toxicity of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazoles S-derivatives is found to be within the range of 193–770 mg/kg. Some patterns of "structure-acute toxicity" are revealed.

In recent years we see significant increase of natural and technogenic situations that lead to disorders of functional and metabolic processes of central nervous system and cardiovascular diseases, including acute cerebrovascular accident. The leading factor in vascular brain pathology is hypoxia. Currently all body states, in which we see any reason decrease of oxygen delivery to tissues is considered as hypoxia. Paying into account the fact that available pharmacotherapeutic agents for the oxygen deficiency treatment tend to have limited efficacy, narrow range of active doses and often cause undesirable side effects, the special attention is paid to drugs that have an antihypoxic action and exclude the above mentioned effects. Aim. To study antihypoxic actions for the first time synthesized derivatives of 1,2,4-triazoles and to find the "structure - action" dependence. Materials and methods. Antihypoxic activity of 1,2,4-triazoles derivatives was studied at modeling hypoxia with hypercapnia. Rats were placed in same volume (1330 ml) sealed up jars, then overturned them down and put in a cell with water to prevent the flow of air. As a comparison drug in the study we used mexidol 100 mg / kg. Results. The study has identified three compounds that extend the comparison drug mexidol and prolong the life expectancy of 59.94 %, 47.79% and 53.31% (compounds 1, 2, 5, respectively). While mexidol was 42.54%. After analyzing the data and chemical structure of the synthesized compounds we have established some relative patterns between chemical structure and antihypoxic actions of 1,2,4-triazoles derivatives. Conclusions. As the result of the study, we have discovered the compound that exceeds the referent drug mexidol on 17.4%. In the study of the acute toxicity of 1,2,4-triazoles derivatives it was found that all compounds belong to IV Class of toxicity (LD50 = 331-770 mg / kg). The presence of two halogen atoms in the molecules of benzylidenhydrazides of 4-R-5-(thiophene-2-ylmethyl)-1,2,4-triazol-3-il) thioacetic acid shows expressive antihypoxic action.

Aim. Analysis of the scientific literature over the past decade has shown that large synthetic possibilities towards creating new and effective drug substances have heterocyclic compounds, in particular the derivatives of 1,2,4-triazole. 1,2,4-Triazole is a structural fragment of many synthetic drugs. The special interest cause ylidene hydrazides of 2-(5-R-1,2,4-triazole-3-ylthio)acetic acids as potential biologically active compounds, among which highly effective medicines can be found. With the aim of finding new biologically active compounds the derivatives of 2-((4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)aceticohydrazides have been synthesized, their physical-chemical properties have been studied with the use of modern methods, namely elemental analysis, IR,1H-NMR spectroscopy, and their individuality by HPLC-MS. Materials and methods. N'-R1-еden-2-((4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)aceticohydrazides were received by adding aromatic (2-BrC6H4, 2,3-(OCH3)2C6H3, 3,5-(OCH3)2C6H3, 4-N(CH3)2C6H4, 3,4-F2C6H3, 2-NO2C6H4,4-NO2C6H4, 4-OHC6H4, 2-OHC6H4, 4-FC6H4, 2-CI-6-FC6H3) or heterocyclic (2-SC4H3, 5-NO2-2-C4H2O) aldehyde to an equivalent amount of the appropriate 2-((4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)aceticohydrazide in the acetic acid medium. The study of physical-chemical properties of obtained compounds was carried out according to the methods outlined in SPU. Chromato-mass-spectral studies were performed on hazarding chromatograph Agilent 1260 Infinity HPLC equipped with mass spectrometer Agilent 6120 with ionization in electro-spray (ESI). Conclusion. This suggests the possibility for further study of biological action of the synthesized compounds. As a result of studies the N'-R1-eden-2-((4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-yl)thio)aceticohydrazides have been synthesized and their physical-chemical properties have been studied.

The amount of antibiotics has increased over the past decade. This also resulted in increase of microorganisms’ resistance to this class of drugs. Therefore, the synthesis of new compounds that have exhibited antimicrobial and antifungal activity and low level of side effects is an important issue of modern pharmacy. The 1,2,4-triazole system is very promising in this aspect. The aim was to study the antimicrobial and antifungal activity of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol and 3-(alkylthio)-4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole. Methods and results. In the study "serial dilutions" method has been used. The criteria for the activity of given compound was the minimum inhibitory concentration (MIC) which is the lowest concentration of drug that inhibits the growth of the test culture and the minimum bactericidal concentration (MBC) which is the lowest concentration of drug that causes bactericidal effect. Test compounds are derivatives of 4-R-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole-3-thiol and 3-(alkyl-thio)-4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole which exhibit antifungal and antimicrobial activity. Conclusion. The most active of the studied 1,2,4-triazole derivatives is 4 (4-methyl-3-(octylthio)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazole), which manifests as antifungal and antimicrobial activity. Some regularity between structure and action has been investigated.

Aim. Selection, synthesis and biological properties of new compound play major role in creating original medicines. Methods and results. Therefore, to find new bioactive compounds 3-(alkylthio)-4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazoles, where R - methyl, ethyl, phenyl, have been synthesized, by alkylation reaction of 4-R-5-(thiophene-2-ylmethyl)-4H-1,2,4-triazole-3-thiols with 1-bromobutane, or 1-bromopentane, or 1-bromohexane, 1-bromoheptane, 1-bromooctane, 1-bromononane, 1-bromodekane in the n-butanol medium and their physical-chemical properties have been studied using modern physical-chemical methods of analysis, elemental analysis, IR spectroscopy, and their individuality using HPLC-MS. Conclusion. This suggests the possibility of further studying the biological effect of the synthesized compounds.