Non-annulated tetrazole-containing polynuclear compounds, in which heterocyclic fragments are bound by an acetamide linker were synthesized. The synthesis was accomplished by acylation of 2-hydrazinyl-4,6-dimethylpyrimidine, 4-amino-4H-1,2,4-triazol-3-thiol, 2-[(1-amino-1H-tetrazol-5-yl)thio]-N-tert-butylacetamide, 1-methyl-1H-tetrazol-5-amine, and 2-methyl-2H-tetrazol-5-amine with one key reagent, (5-phenyltetrazol-2-yl)acetyl chloride. Preliminary in silico studies showed the presence of the in vivo antidiabetic (diabetes 2 type) activity in N′-(4,6-dimethylpyrimidin-2-yl)-2-(5-phenyl-2H-tetrazol-2-yl)acetohydrazide. N-(3-Mercapto-4H-1,2,4-triazol-4-yl)-2-(5-phenyl-2H-tetrazol-2-yl)acetamide demonstrated minimal hypoglycemic activity in in vivo studies, at the same time, it showed pronounced activity as a drug for combating obesity.

Rapid processes of tetrazole decomposition serve as sources of chemical energy stored in the five-membered ring, as well as gaseous products, primarily molecular nitrogen. Due to these properties, energetic tetrazole derivatives have found applications in various fields of science, engineering and technology, for example as components of energetic materials and products, as well as in emergency rescue equipment. The review presents an alternative view of the processes of tetrazoles decomposition, focusing on the diversity, differences, and similarities of the mechanisms and degradation products formed under the action of external energy sources. Some of these products are valuable reagents for the synthesis of previously inaccessible substances, as well as promising objects of analytical, medical, and bioorthogonal chemistry. Bibliography includes 140 references.

The key to import substitution of medicines is the organization of full-cycle production at Russian facilities, the basis of which is the organic synthesis of active pharmaceutical ingredients (APIs). This review examines the principal problems in the development of the production of APIs for medicines in Russia and the possible approaches toward addressing them under modern conditions.

A novel method for the synthesis of 1,2,4-triazolo[1,5-d][1,2,4]triazine-2-amines by solvent-free thermolysis of the 1H-tetrazole-5-amine in presence of the 1,2,4-triazine-5-carbonitriles has been proposed. A mechanism of found interaction has been suggested.

Highly purified 5-vinyl-1H-tetrazole was synthesized, which is in great demand in modern medicine and industry as a monomer for obtaining nitrogen-rich macromolecular compounds and a reagent for the complete synthesis of biological compounds. The molecular structure was studied experimentally with sequential X-ray diffraction analysis and theoretically with ab initio quantum chemical calculations. The data from differential scanning calorimetry, nuclear magnetic resonance (1H, 13C, 1H-15N, HMBC), high-resolution mass spectrometry and vibrational spectroscopy were analyzed. The results are useful for evaluating the possibility of extending the polymerization of 5-vinyl-1H-tetrazole to synthesize polymers with predictable molecular weight and thermodynamic parameters.

3-(5-Phenyl-2H-tetrazol-2-yl)pyridine was synthesized by treating 5-phenyl-1H-tetrazole with pyridin-3-ylboronic acid under Chan–Evans–Lam coupling conditions. The structure and identity were confirmed by 1H, 13C-NMR spectroscopy, IR spectroscopy, UV–Vis spectroscopy, high-resolution mass spectrometry, and TLC. The molecular structure was studied experimentally by sequential X-ray diffraction analysis and theoretically by DFT B3LYP quantum chemistry calculation.

A novel method for synthesizing 1,2,4-triazole- and tetrazole-containing 4H-thiopyrano[2,3-b]quinolines using a new combination of the thio-Michael and aza-Morita–Baylis–Hillman reactions was developed. Target compounds were evaluated for their cytotoxicities and antiviral activities against influenza A/Puerto Rico/8/34 virus in MDCK cells. The compounds showed low toxicity and some exhibited moderate antiviral activity. Molecular docking identified the M2 channel and polymerase basic protein 2 as potential targets. We observed that the antiviral activity of thiopyrano[2,3-b]quinolines is notably affected by both the nature and position of the substituent within the tetrazole ring, as well as the substituent within the benzene moiety of quinoline. These findings contribute to the further search for new antiviral agents against influenza A viruses among derivatives of thiopyrano[2,3-b]quinoline.

Tetrazole heterocycle is a promising scaffold in drug design, and it is incorporated into active pharmaceutical ingredients of medications of various actions: hypotensives, diuretics, antihistamines, antibiotics, analgesics, and others. This heterocyclic system is metabolically stable and easily participates in various intermolecular interactions with different biological targets through hydrogen bonding, conjugation, or van der Waals forces. In the present review, a systematic analysis of the activity of tetrazole derivatives against type 2 diabetes mellitus (T2DM) has been performed. As it was shown, the tetrazolyl moiety is a key fragment of many antidiabetic agents with different activities, including the following: peroxisome proliferator-activated receptors (PPARs) agonists, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase (AR) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, G protein-coupled receptor (GPCRs) agonists, glycogen phosphorylases (GP) Inhibitors, α-glycosidase (AG) Inhibitors, sodium glucose co-transporter (SGLT) inhibitors, fructose-1,6-bisphosphatase (FBPase) inhibitors, IkB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) inhibitors, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In many cases, the tetrazole-containing leader compounds markedly exceed the activity of medications already known and used in T2DM therapy, and some of them are undergoing clinical trials. In addition, tetrazole derivatives are very often used to act on diabetes-related targets or to treat post-diabetic disorders.

New tetrazole-containing derivatives of morpholin-4-yl-1,3,5-triazine and 4-methylpiperidin-1-yl-1,3,5-triazine were synthesized. The cytotoxic activity of the obtained compounds against human liver Huh-7 and human lung A549 tumor cell lines was tested by MTT assay. It was demonstrated that these substances do not show pronounced cytotoxic effects. The most significant antitumor activity was exhibited by 1,3,5-triazine containing a 5-phenyltetrazol-2-ylacetohydrazide moiety and a 4-methylpiperidine ring as substituents, as well as by 1,3,5-triazine bearing a 5-methyl-1H-tetrazol-1-ylacetohydrazide moiety and two morpholine rings. For these compounds, the interaction with DNA was studied by UV spectroscopy. Also, for N'-(4,6-dimorpholino-1,3,5-triazin-2-yl)-2-(5-methyl-1H-tetrazol-1-yl)acetohydrazide, the DNA binding constant was determined (Kbin 9.02×104 M−1), and the ability to inhibit the tyrosine kinase domain of the cell-surface receptors was evaluated. It was shown that the studied tetrazole-containing 1,3,5-triazine derivatives do not exhibit antioxidant activity against NO radicals and do not cause photoinduced hemolysis.

The synthesis, identification and evaluation of the biological activity of a new non-covalent conjugate based on graphene oxide and (5-{[4,6-di(aziridin-1-yl)-1,3,5-triazin-2-yl]-amino}-2,2-dimethyl-1,3-dioxan-5-yl)methyl (5-phenyl-2H-tetrazol-2-yl)acetate were carried out. It was shown that the synthesized nanoconjugate is hemocompatible over the entire studied concentration range (10–100 μm) and demonstrates antiradical activity under irradiation. In addition, the conjugate exhibits cytotoxicity against A549 and HeLa cell lines with IC50 values of 4.0 and 73.7 μm, respectively.

New tetrazole-containing derivatives of 2,4-diamino-1,3,5-triazine were synthesized. The cytotoxic activity of the obtained compounds against Huh-7 and HeLa tumor cell lines was studied by the MTT test. The most significant antitumor activity was shown by 1,3,5-triazines containing a 5-phenyltetrazol-2-ylacetohydrazide fragment. The resulting compounds showed practically no cytotoxic effect on non-tumor cells of the human embryonic kidney line HEK293.

The kinetics and mechanism of the Curtius rearrangement of m-nitrobenzoyl azide in aqueous solutions of sulfuric acid of various concentrations has been studied. An increase of the acidity of the reaction solution an increase in the acidity of the reaction solution leads to an acceleration of the rearrangement. The rate-limiting step of the reaction is the rearrangement of the protonated form of m-nitrobenzoyl azide to the corresponding isocyanate

3-{[(1-Methyl-1 H -tetrazol-5-yl)imino]methyl}quinoline-2-thiol and 3-{[(2-methyl-2 H -tetrazol-5-yl)imino]methyl}quinoline-2-thiol were synthesized. The sequence of the thiol-Michael reaction and the (aza)-Morita–Baylis–Hillman reaction yielded 4-[(1-methyl-1 H -tetrazol-5-yl)amino]-2-phenyl-4 H -thiopyrano[2,3- b ]quinoline-3-carbaldehyde, 4-[(2-methyl-2 H -tetrazol-5-yl)amino]-2-phenyl-4 H -thiopyrano[2,3- b ]-quinoline-3-carbaldehyde, and 4-hydroxy-2-phenyl-4 H -thiopyrano[2,3- b ]quinoline-3-carbaldehyde. Cytotoxicity and antiviral activity against the A/Puerto Rico/8/34 (H1N1) influenza virus strain in MDCK cell culture were determined for the obtained compounds. The study showed that the replacement of the hydroxyl group in 4-hydroxy-2-phenyl-4 H -thiopyrano[2,3- b ]quinoline-3-carbaldehyde with a 1-methyl- or 5-amino-2-methyltetrazolyl fragment decreased antiviral activity. At the same time, 3-{[(1-methyl-1 H -tetrazol-5-yl)imino]-methyl}quinoline-2-thiol has a higher activity than 3-{[(2-methyl-2 H -tetrazol-5-yl)imino]methyl}quinoline-2-thiol. This fact indicates a possible relationship between the arrangement of substituents in the tetrazole ring and the antiviral activity of the tested heterocyclic system.

The kinetics of the nitration reaction of m-nitrobenzoic acid with nitric acid in a sulfuric acid medium of various concentrations was studied by UV spectroscopy. The observed differences in the rate of nitration of m-nitrobenzoic acid from the nitration of alkylbenzenes are associated with the electron-withdrawing nature of the carboxyl group, as well as with its protonation. During the reaction, not only 3,5-dinitrobenzoic acid is formed, but also products with significantly higher molar absorption coefficients

This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level.

({5-[4,6-Di(aziridin-1-yl)-1,3,5-triazin-2-yl]amino}-2,2-dimethyl-1,3-dioxan-5-yl)-methyl 2-(5-phenyl-2H-tetrazol-2-yl)acetate was synthesized and characterized. The interaction of the obtained tetrazole-containing 2-amino-4,6-di(aziridin-1-yl)-1,3,5-triazine derivative with DNA was studied by UV spectrophotometry, circular dichroism spectroscopy, and isothermal calorimetry. The values of binding constants (9.65·108 L mol−1, UV spectrophotometry; 4.08·108 L mol−1, isothermal calorimetry) of the 1,3,5-triazine derivative to DNA attests to efficient binding and formation of stable associates with the biopolymer. The addition of the tetrazole-containing 1,3,5-triazine derivative to a DNA solution has virtually no effect on the DNA melting point. The tetrazole-containing 1,3,5-triazine derivative exhibits a cytostatic effect on SK-HEP-1 human hepatic adenocarcinoma cells (half-maximal inhibitory concentration IC50 22.2 mmol L−1) and T98G human glioblastoma cells (IC50 44.9 mmol L−1).

The reactions of substituted 5-aminopyrazoles and 5-amino-1,2,4-triazole with 3-(ethoxymethylidene)acetylacetone, as well as with ethyl acetylpyruvate sodium salt, were employed to synthesize a number of substituted pyrazolo[1,5-a]- and 1,2,4-triazolo[1,5-a]pyrimidines. The alkylation of the synthesized pyrazolo[1,5-a]- and 1,2,4-triazolo[1,5-a]pyrimidines with methyl iodide and ethyl iodide was studied. Evidence was obtained from the NMR (NOESY) spectra that pyrazolo[1,5-a]pyrimidines are alkylated at the nitrogen atom of the pyrimidine ring, while the alkylation of 1,2,4-triazolo[1,5-a]pyrimidines involves the triazole N-3 atom.

Catalytic reduction reactions play a major role in modern chemistry and are often based on hydrogen gas as a reducing agent. However, the high reactivity of hydrogen is often accompanied by low selectivity on the simple catalysts. Herein, we showed that the usage of syngas as a reducing agent can be a more efficient and selective strategy. Based on control experiments, a plausible mechanism was proposed to explain the superior performance of syngas. The versatility of this approach was demonstrated by successful application to three reactions using tion, and the tandem CH-reductive alkylation-hydrolysis-decarboxylation. Catalyst turnover numbers up to 30,000 were achieved. Moreover, the developed strategy showed improved selectivity and functional group compatibility as compared to the use of hydrogen gas.