Search

Аbstract Significance. Nowadays non-steroidal anti-inflammatory drugs have found a wide application in treatment of medical conditions. Despite the clinical effectiveness of non-steroidal anti-inflammatory drugs, their administration is followed by a set of side effects. With aim to reveal the substances with a potency of altering pain threshold in animals, the action of 4-amino-5-methyl-4H-1,2,4-triazol-3-thiones on the nociceptive system in conditions of thermal irritation of rats’ extremities was studied. Aim. Study of the analgesic activity of 4-amino-5-methyl-4H-1,2,4-triazol-3-thiones. Materials and methods. Analgesic activity of the synthesized compounds was evaluated in terms of the set of experiments conducted on white rats of 180-240 g weight. The primary pain threshold after the administration of the substances was assessed using a “hot plate” test, involving a metal plate heated at 55 oC as an irritator. The time of the corresponding response (paw licking, jumping out, squeaking) was measured in seconds. Analgesic activity was assessed by observations of the alterations of pain threshold of the group of studied animals to whom the substances of research were administrated, comparing results with the control group and expressing them in percent. Results. According to the results, it was concluded that the compound of 4-(3,4-dimethoxebenzylidenamino)-5-methyl-4H-1,2,4-triazol-3-thione was the most potent, which reduced the sensitivity to thermal irritation of extremities in the group of animals by 127.78%; that said, its activity is higher than that for the reference drug Analgin, which was also evaluated in a “hot plate” test. It was established that substance (IV) was slightly more active than the reference drug Analgin, demonstrating 121.11% of analgesic activity. Processing of the experimental data revealed some dependencies between the chemical structure and pharmacological activity of the substances of research. Conclusion. The obtained results demonstrate that analgesic activity is existent among the set of 1,2,4-triazole derivatives, which mandates a deeper research of the effectiveness and safety of the most active compounds among the studied compounds.

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 successful use of drugs, derivatives of 1,2,4-triazole, creates the conditionsfor the production and investigation of properties of new derivatives of this heterocyclic system. The aim of this work was synthesis and study of physical and chemical properties of new derivatives of 1,2,4-triazole-3-thiol containing synthon of pyrrole. The object of the study was a 4-phenyl-5-(pyrrol-2-yl)-1,2,4-triazole-3-ylthio-R-carbothioamides. To achieve this goal it was necessary to solve following tasks: to conduct the selection of the optimum base structure to determine the most efficient way of chemical modification of the precursor of targeted synthesis, to carry out selection of necessary methods of synthesis, to investigate the physico-chemical properties and to set the structure of the obtained compounds. The synthesis of target products of the reaction was carried out using as starting material pyrrole, which with using the form non-catalytic form of reaction of the Fridel-Crafts was transformed into 2,2,2-trichloro-1-(pyrrol-2-yl), ethanol. The resulting material in the result of reaction of hydrazinolysis was converted into the pyrrol-2-carbohydrazide. The obtained intermediate product was used in the reaction of nucleophilic joining of phenylisothiocyanate with subsequent intramolecular alkaline heterocyclization. Synthesized thiol was used in the reaction of alkylation. The structure of the obtained substances are confirmed by using elemental analysis, 1H-NMR-spectroscopy, and their individuality – chromatographic methods of analysis. The resulting substances are an interesting object for further studies, especially biological activity.

Today, an increase of natural and technogenic situations leads to the disorders of the central nervous system, functional-metabolic processes, vascular diseases, in particular, acute cerebral blood flow disorders. In addition, the changes occurring on the molecular and cellular levels are in the basis of the functional violations of individual systems and the organism as a whole. Hypoxia not only complicates the disease course, but in most cases, determines its outcome. The important role in the fight against hypoxia belongs to antioxidants, which improve the circulating oxygen utilization by the body, reduce its need for the organs and tissues, which is not only expedient but necessary for the treatment of many acute and chronic pathological processes. So, the frequency of the hypoxic states and a wide range of factors causing them determine the relevance of new ways and methods finding to overcome the oxygen deficiency. The aim of this work is the purposeful search of some 5-[((5-(adamantane-1-yl)-4-R-4H-1,2,4-triazole-3-yl)thio)methyl]-N-R1-1,3,4-thiadiazole-2-amines and 5-[((5-(adamantane-1-yl)-4-R-4H-1,2,4-triazole-3-yl)thio)methyl]-4-R1-4H-1,2,4-triazole-3-thiols, the study of their physical and chemical properties and pharmacological screening of the antihypoxic activity of the obtained compounds. Materials and methods. The study of physical and chemical properties was conducted on certified and licensed modern equipment. Antihypoxic activity was studied during the modeling process of hypoxia with hypercapnia. Mexidol was used as a comparison drug in studies at a dose of 100 mg/kg. Results. As the result of the study, it was found that the synthesized compounds and the comparison drug influenced on rats’ life span differently. Compounds, the antihypoxic activity of which exceeded control have been discovered, and others’ were at the level of Mexidol. A number of compounds showed a somewhat less activity in comparison with control, and two compounds, among the investigated ones were weaker then comparison drug action, but they did not reduce the life expectancy of the investigated groups in comparison with control. The effect of the remaining compounds on the lifetime of the investigated group was at the level of control group that received the physiological solution. Conclusions. A series of new compounds of derivatives among 5-[((5-(adamantane-1-yl)-4-R-4H-1,2,4-triazol-3-yl)thio)methyl]-N-R1-1,3,4-thiadiazole-2-amines and 5-(5-(adamantane-1-yl)-4-R-4H-1,2,4-triazole-3-yl)thio)methyl)-4-R1-4H-1,2,4-triazole-3-thiols have been synthesized, the structure of which has been confirmed with the help of modern physical and chemical methods of analysis. The most active compounds among the studied ones were 3a and 2a, their antihypoxic activity exceeds control on 37.86 % and 36.30 % and Mexidol is on 7.35 % and 5.79 % respectively.

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.

Thanks to the rapid development of science, humanity has achieved remarkable success in various fields. This also applies to the synthesis of biological compounds. Over the centuries, scientists have invented many methods and drugs that are being actively used to date. Derivatives of 1,2,4-triazole can be the foundation for the manufacture of new native drugs that will compete with foreign ones. The aim of work was synthesis and confirmation the structure of 2-((4-(R-amino)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetate acids salts. Materials and methods. As starting substances we used 2-((4-(R-amino)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetic acids, which were synthesized by previously described methods. The structure of synthesized compounds was confirmed by the complex use of modern physical-chemical methods of analysis: elemental analysis, 1H-NMR spectroscopy, HPLC-MS. Results. Salts of 2-((4-(R-amino)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetic acids were synthesized by the interaction of the appropriate acids with organic (morpholin, methanamin, 2-hydroxyethanamin), inorganic basics (aqueous ammonia solution, sodium hydroxide) and salts (zinc sulfate, ferrum (III) chloride, magnesium sulfate, copper (II) sulfate) in alcoholic or aqueous media. Conclusions. A series of novel 2-((4-(R-amino)-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-yl)thio)acetic acids salts were synthesized. The structure of synthesized compounds is established using modern physical-chemical methods of analysis.