Analysis of biological properties of 1,2,4-triazole-containing compounds (literature review)

In the latest conditions of development and formation of the pharmaceutical industry, the introduction of new synthetic medicines requires continuous monitoring of the quality and safety of their use. For many years, synthetic drugs have remained an essential tool in the prevention and control of diseases of various etiologies. Among the synthetic class of substances, first of all, those that are low-toxic, safe, and effective deserve attention. In recent decades scientific publications prove the prospects of searching for new biologically active compounds among derivatives of 1,2,4-triazoles with fragments of various heterocyclic systems. Scientists claim that the combination of several structural fragments of heterocycles in one molecule leads to the emergence of new types of biological action, and sometimes to an increase in known pharmacological effects. At the same time, the synthesized compounds belong to the class of low-toxic or practically non-toxic substances. The aim of our work is to analyze foreign and native sources on the biological activity of 1,2,4-triazole derivatives. Conclusions. Among these derivatives, molecules that exhibit broad antifungal and antimicrobial activity, antitubercular, antiviral, actoprotective, antihypoxic, analgesic effects, etc. were found. After analyzing the known data, a number of «structure-action» regularities were established. The obtained results will be useful for further research work of scientists.

Актуальные вопросы фармацевтической и медицинской науки и практики. 2022. Т. 15, № 1(38). С. 102-106 According to the World Health Organization, people's ave rage life expectancy has increased over the past fifty years. Achievements in the field of Medicine and pharmacy played not the least role in this. A qualitative leap occurred with the rapid development of chemistry, it became possible to install the active components of many drugs and introduce the first purely synthetic drugs. Later on, synthetic chemists began to practice various chemical modifications of already existing active molecules. But despite all the scientific achievements, the problem of finding new highly effective biologically active substances still does not lose its relevance. The reason for this is the low effectiveness or lack of it in wellknown drugs used for the prevention and treatment of a few pathological conditions, as well as the presence of side effects.

Aim
The aim of our work was to summarize scientific data in recent years concerning the biological properties of 1,2,4tri azole derivatives. This work will be useful for synthetic chemists who are engaged in the design and development of new compounds consisting of a 1,2,4-triazole core, in order to obtain new and better tools in terms of efficiency and safety.
Scientists have proven that chemical structures containing fragments of 1,2,4-triazole and quinoline have a wide range of chemotherapeutic properties [1], they have demonstrated high antibacterial activity against both drug-sensitive and drug-resistant bacteria. Establishing a structure-activity rela tionship (SAR) is necessary for further rational development of 1,2,4triazolecontaining synthetic systems against sensi tive and Drug-Resistant Pathogens. It has been experimentally proven that a small number of metal ions included in the struc ture of 1,2,4-triazole increases the activity of molecules [2]. In particular, the Schiff bases having-nucleophilic substituent's OH, -SH, and -NH2 in the ortho-position azomethine group have the corresponding structures to coordinate with metal ions, forming more stable metalal-chelates. The unique properties of chelates, which act as an intermediate bond between conventional organic and inorganic compounds, provide innovative opportunities in the field of pharmaceutical chemistry. Bio-organic compounds play an important role in the development of a new strategy for creating effective drugs, in particular phenylenediamine derived mono-and bis-Schiff bases, 2-{[(4-aminophenyl)imino]methyl}-6-methoxyphe nol and 2,2'-{benzene-1,2-diylbis[nitrilomethylylidene]} bis(6-methoxyphenol) [2]. The authors identified a few bio logical activities in such molecules: antifungal, antibacterial, antioxidant.
Bacterial infections are mainly caused by Gram-positive and Gram-negative microorganisms due to the intensive reproduction of harmful strains. Antibiotics can disrupt the processes necessary for the growth and proliferation of bacterial cells, and they are an effective weapon for fighting bacterial infections. However, excessive and improper use of antibiotics leads to an increase in antibiotic resistance among microorganisms, which creates an urgent need to develop new effective drugs.
Tuberculosis (TB) is an infectious disease caused primarily by Mycobacterium tuberculosis and is responsible for 4.000 deaths per day in 2019 worldwide [6]. The authors proved the possibility of effective control of this bacterial infection with the help of new derivatives of thiazole, thiotriazole, and semicarbazones [6]. Scientists have also developed a series of new hybrids 1,2,4-triazole-norfloxacin. The compounds showed a higher antibacterial effect than norfloxacin against gram-positive and gram-negative bacteria [7]. In addition, hemolysis was not observed at a concentration of 64 micrograms/ml, which indicates the good biocompatibility of molecules. Molecular docking showed the lowest binding energy from -9.4 to -9.7 kcal/mol. It was also predicted that all compounds exhibit excellent affinity for bacterial topoisomerase IV [7]. Original and interesting research will be offered by scientists developing coumarin-containing heterocyclic compounds [8]. The possibility of combining coumarin and 1,2,4-triazole fragments to solve the problem of creating innovative antibacterial derivatives has been proven by a team of scientists [8]. Other authors have developed a series of 4-amine-3-hydrazino-5-mercapto-1,2,4-triazole Schiff bases -effective antifungal agents [9].
A group of scientists conducted interesting studies on the an tiviral activity of 1,2,4-triazole-containing compounds [19]. The activity was studied against viruses, hepatitis C, influenza A, and influenza B, herpes of the first and second types, etc. As a base agent, the already well-known drug Ribavirin was chosen, in the structure of which there is a 1,2,4-triazole frag ment. Ribavirin analogs were obtained that have a vinylaryl substituent in the fifth position of the triazole ring (E and Z isomers). After studying this activity, it became known that only E-isomers are highly active, while Z-isomers are inactive. After analyzing the structure-action, it became known that the high activity of E-isomers is associated with a rigid bond between triazole and the aryl ring, as well as due to the presence of a lipophilic substituent in the para-position of the aryl ring [18].
Another group of scientists obtained a few acetamide-sub stituted analogs of Doravirin, which is a nucleoside reverse transcriptase inhibitor and is used to treat HIV infections [20]. Most of the obtained compounds showed inhibitory proper ties against HIV, but the compound that had a 1,2,4-triazole substituent in the amide fragment showed a result exceeding the comparison agent Doravirin.
Condensed derivatives of 1,2,4-triazole, namely stable σ-aducts of 1,2,4-triazolo[5,1-c]triazines and 1,2,4-triazo lo-[1,5-a] pyrimidines with various polyphenols, were also studied for antiviral activity [21]. The resulting triazoloazines modified with fluoroglycin showed high activity against the in fluenza A virus, after molecular modeling, it was found that their action is directed against viral hemagglutinin, a protein that ensures the ability of the virus to attach to the host cell.
The search for new promising compounds among 1,2,4-tri azole derivatives is carried out not only by foreign scientists but also by domestic ones, in particular, scientists of Zaporizhzhia State Medical University have been obtaining and in vestigating new molecules based on 1,2,4-triazoles for many years. Over the years, a considerable number of interesting compounds have been obtained, which today have practical value and are used in various industries.
In the modern world, the majority of society lives at a fast pace, constant physical and emotional stress, is influenced by technological progress, as well as global urbanization, all this together leads to stress, anxiety and general fatigue of people. As a result, there is constant fatigue, a sharp decrease in the protective and adaptive mechanisms of the body, immu nity, which in turn contributes to the emergence of a number of other negative processes in the body. That is why, recently, the general interest in actoprotective agents has been increa sing, because these are drugs that help preserve and increase the body's resistance to physical exertion, increase efficiency.
The obtained results are undoubtedly significant for pharmaceutical science, as fungal infections are widespread and have the ability to develop resistance to drugs that are presented in the pharmaceutical market.
Among all diseases, heart disease ranks first in mortality. It has recently become known that a significant role in myocar dial damage is played by the inability of the cardiomyocyte energy system to utilize oxygen. As a result, the formation of free radical, active forms of oxygen increases, which con tributes to damage to functionally important proteins, nucleic acids, and other structures of cardiomyocytes, which inevi tably leads to the development and progression of ischemic myocardial damage. In this regard, pharmacological drugs for antiischemic protection of the myocardium -antihypoxantsare currently being actively developed and implemented in clinical practice.
However, it should not be forgotten that the most com mon cause of cardiovascular diseases is atherosclerosis. Atherosclerosis is a disease that affects arterial vessels due to the proliferation of connective tissue and the formation of arterial plaques. This pathology leads to heart attacks and strokes.
Until recently, this disease was considered a disease of old age, but every year this disease "gets younger". That is why it is very important to look for new compounds that will show hypolipidemic activity. Among the morpholinium salts of 2-(4-R-5-R 1 4H-1,2,4-triazole-3-ylthio)acetic acids, compounds were found that showed quite high results [15]. The formation of atherosclerosis was determined by the level of several indicators: total cholesterol, β-lipoproteins, tri glycerides, and cholesterol levels in aortic tissues. Accord ing to the results of the research, interesting regularities of structure-action dependence have been established. Thus, in the transition from 2methylphenyl to 4bromophenyl and 2methoxyphenyl radicals at the position of the N4 atom of the nucleus of 1,2,4-triazole in the morpholine molecule 2-(5-(4-pyridyl)-4-R-1,2,4-triazole-3-ylthio)acetate a gradual loss of hypocholesterolemic activity was observed in. When replacing a methyl radical with phenyl and 2-methylphe nyl radical at the position of the atom of the 1,2,4triazole nucleus in the morpholine molecule 2-(5-(4-pyridyl)-4-R-1,2,4-triazole-3-ylthio)acetate showed a gradual loss of hypotriglyceridemic activity. A total of twelve compounds were analyzed, of which morpholine 2-(5-(2-pyridin-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate showed the highest activity against all indicators.
The search for substances that have analgesic effects has long been a priority in pharmacology because pain is a key symptom of most diseases. Analgesics are a group of drugs used to relieve pain caused by inflammation or damage to tissues and organs. There are many members of this pharmacological group, both synthetic and herbal, but they all have a few contraindications and side effects. It is known that condensed 1,2,4-triazole derivatives have a high analgesic effect [16]. Given the fact that most 1,2,4-triazole derivatives are low-toxic compounds, the search for deriv atives of this series of new analgesics is promising. Native scientists have combined the pyrimidine and triazole cycles to obtain new compounds [17]. As a result, a few 5-me thyl-3-aryl-[1,2,4]triazolo[4,3-a]pyrimidin-7-ol derivatives were obtained, the effectiveness of which outperformed that of the reference drug (ketorolac). The hot plate test was used to determine the latent reaction period. The highest activity was determined for a compound containing a methyl group in the fourth position of the aryl substituent, and when halogens are introduced into the aryl moiety, a decrease in this effect is observed.

Conclusions
In the course of our work, scientific works of native and foreign scientists were processed in order to analyze and generalize known data on the biological activity of a number of derivatives of 1,2,4-triazole. The already obtained results indicate the prospects of these derivatives because they demonstrate a fairly wide range of biological activities and low toxicity.