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A series of novel water-soluble salts of benzofuroxans was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan with various amines. The salts obtained showed good effectiveness of the pre-sowing treatment of seeds of agricultural crops at concentrations of 20–40 mmol. In some cases, the seed treatment with salts leads not only to improved seed germination, but also to the suppression of microflora growth. Additionally, their anti-cancer activityin vitrohas been researched. The compounds with morpholine fragments or a fragment of N-dimethylpropylamine, demonstrated the highest cytotoxic activity, which is in good correlation with the ability to inhibit the glycolysis process in tumor cells. Two compounds 4e and 4g were selected for further experiments using laboratory animals. It was found that the lethal dose of 50% (LD50) is 22.0 ± 1.33 mg/kg for 4e and 13.75 ± 1.73 mg/kg for 4g, i.e., compound 4e is two times less toxic than 4g, according to the mouse model in vivo. It was shown that the studied compounds exhibit antileukemia activity after a single intraperitoneal injection at doses from 1.25 to 5 mg/kg, as a result of which the average lifespan of animals with a P388 murine leukemia tumor increases from 20 to 28%. Thus, the water-soluble salts of benzofuroxans can be considered as promisingcandidates for further development, both as anti-cancer agents and as stimulants for seed germination and regulators of microflora crop growth.

В настоящее время разработаны биосенсоры с использованием одного, двух или даже нескольких ферментов, иммобилизованных на поверхности электрода, но на текущий момент таких работ сравнительно мало, еще меньше известно работ по применению каскадных реакций, катализируемых иммобилизованными мультиферментными системами из-за сложности изготовления мультиферментных сенсоров: с каждым ферментом требуется работать индивидуально. При химической иммобилизации каждый фермент нужно модифицировать и прикреплять к подложке, при физической иммобилизации время ответа может быть довольно долгим. Изготовление мультиферментного сенсора является сложной задачей, решение которой, в свою очередь, откроет новый спектр клинических и фармацевтических применений. Метод иммобилизации ферментов позволяет многократно и в течение длительного времени использовать для измерения одни и те же молекулы фермента, помещенные в микрокапсулы полимерного покрытия. Проведение измерений концентраций обусловлено рядом свойств биочувствительного покрытия: хорошая проницаемость полиэлектролитных слоев для глюкозы и продуктов ее разложения глюкозооксидазой, непроницаемостью этих слоев для фермента и сохранения ферментом, находящимся в ячейках покрытия, высокой активности

This research focuses on the X-ray structure of 4,6-dichloro-5-nitrobenzofuroxan 1 and of some of its amino derivatives (4a, 4e, 4g, and 4l) and on DFT calculations concerning the nucleophilic reactivity of 1. We have found that by changing the solvent used for crystallization, it is possible to obtain 4,6-dichloro-5-nitrobenzofuroxan (1) in different polymorphic structures. Moreover, the different torsional angles observed for the nitro group in 1 and in its amino derivatives (4a, 4e, 4g, and 4l) are strictly dependent on the steric hindrance of the substituent at C-4. DFT calculations on the course of the nucleophilic substitution confirm the role of the condensed furoxan ring in altering the aromaticity of the carbocyclic frame, while chlorine atoms strongly influence the dihedral angle and the rotational barrier of the nitro group. These results corroborate previous observations based on experimental kinetic data and give a deep picture of the reaction with amines, which proceeds via a “non-aromatic” nucleophilic substitution.

Herein, we report on the reaction of nitro-substituted azidobenzofuroxans with 1,3-dicarbonyl compounds in basic media. The known reactions of benzofuroxans and azidofuroxans with 1,3-dicarbonyl compounds in the presence of bases are the 1,3-dipolar cycloaddition and the Beirut reaction. In contrast with this, azidonitrobenzofuroxan reacts with 1,3-carbonyl compounds through Regitz diazo transfer, which is the first example of this type of reaction for furoxan derivatives. This difference is seemingly due to the strong electron-withdrawing effect of the superelectrophilic azidonitrobenzofuroxan, which serves as the azido transfer agent rather than 1,3-dipole in this case.

In order to obtain novel biologically active substances with various types of activity, hybrid compounds based on 2-(diphenylphosphoryl)acetohydrazide, isatin, and sterically hindered phenols are synthesized. Their molecular and crystal structures are determined by X-ray crystallography.

To obtain new polyfunctional inhibitors of radical-chain oxidative processes, C- and N-benzylation of a number of phosphorylacetic acid hydrazide derivatives is realized in their reactions with 3,5-di-tert-butyl-4-hydroxybenzyl acetate. N-benzylation of mixtures of Z and E isomers of hydrazones of phosphorylacetic acid derivatives proceeds stereoselectively with the formation of only EC=N isomers.

A method was developed for the synthesis of 2-(pyrrolidin-1-yl)pyrimidines and 2-[(4,4-diarylbutyl)amino]pyrimidines by reactions of (hetero)aromatic C-nucleophiles with N-(4,4-diethoxybutyl)pyrimidin-2-amine in the presence of trifluoroacetic acid. The structures of the obtained products were confirmed by methods of IR spectroscopy, 1H and 13C NMR spectroscopy, and X-ray structural analysis.

A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic amines fragments was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the factors affecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored both by its greater stability and the lower activation barrier. Antimicrobial activity of the obtained compounds has been evaluated and some of them were found to suppress effectively bacterial biofilm growth. Fungistatic activity of 4-aminobenzofuroxans were tested on two genetically distinct isolates of M. nivale. The effect of some benzofuroxan derivatives is likely to be more universal against different varieties of M. nivale compared with benzimidazole and carbendazim. Additionally, their anti-cancer activity in vitro has been tested. 4-aminofuroxans possessing aniline moiety showed a high selectivity towards MCF-7 and M-HeLa tumor cell lines. Moreover, they exhibit a significantly lower toxicity towards normal liver cells compared to Doxorubicin and Tamoxifen. Thus, benzofuroxans containing aromatic amines fragments in their structure are promising candidates for further development both as anti-cancer and anti-microbial agents.

The reaction rates for the nucleophilic aromatic substitution of 4,6-dichloro-5-nitrobenzofuroxan 1 with eight aliphatic amines (characterized by very different basicities/ nucleophilicities) and three anilines have been measured in both methanol and toluene. The obtained rates have been related to the basicity (pKaH in water and Kb in benzene) or nucleophilicity (N Mayr constants) of the tested amines. The whole of the obtained kinetic data has furnished useful information on the high nucleophilic reactivity of benzofuroxan derivatives, which has been related essentially to two factors: the high electron-drawing ability/power of the condensed furoxan ring and the low aromatic character of the benzofuroxan system.

It was found that quaternary ammonium salts of benzofuroxan based on o-, m-, and p-dibromoxylenes are formed as a mixture of two tautomers. Only one bromomethyl group participates in the quaternization of benzofuroxan with different dibromoxylenes. Bacteriostatic activity of the most active mixture of tautomers was two and four times higher than the reference drug, chloramphenicol, with respect to Staphylococcus aureus 209p and Bacillus cereus 8035, correspondingly. Hemolysis of these compounds does not exceed 1%, i.e., such compounds are not toxic.

The synthesis of novel 2H-benzimidazole 1,3-dioxides on the basis of o-benzoquinone dioximes interaction with ketones in the presence of acids is described. Nitration of these compounds by nitric acid in acetic acid yields the 5-nitro derivatives of 2H-benzimidazole 1,3-dioxide.

A library of novel 2-(het)arylpyrrolidine-1-carboxamides were obtained via a modular approach based on the intramolecular cyclization/Mannich-type reaction of N-(4,4-diethoxybutyl)ureas. Their anti-cancer activities both in vitro and in vivo were tested. The in vitro activity of some compounds towards M-Hela tumor cell lines was twice that of the reference drug tamoxifen, whereas cytotoxicity towards normal Chang liver cell did not exceed the tamoxifen toxicity. In vivo studies showed that the number of surviving animals on day 60 of observation was up to 83% and increased life span (ILS) was up to 447%. Additionally, some pyrrolidine-1-carboxamides possessing a benzofuroxan moiety obtained were found to effectively suppress bacterial biofilm growth. Thus, these compounds are promising candidates for further development both as anti-cancer and anti-bacterial agents.

Continuing the studies with N- and S-nucleophiles with the aim of synthesizing of novel ‘hybrid’ benzofuroxan compounds, we investigated the interaction of (di)nitrobenzofuroxans with N-, S-containing sterically hindered phenols derivatives. It is interesting to note that in compound 7, containing the N-derivative of a sterically hindered phenol moiety there is one tautomeric form in solution while in compounds 8–9 containing a S-derivative of sterically hindered phenol moieties there are two tautomeric forms in solution.

(Di)chloro(di)nitrobenzofuroxans form substitution products involving carbon atoms with phenolates in isopropyl alcohol medium. In the case of 4,6-dinitro-5,7-dichlorobenzofuroxan, besides replacement of one chlorine atom and the formation of C-bonded product, we observed the hydrolysis of the second chlorine and replacement of it by hydroxyl group. Products of reaction of 4,6-dichloro-5-nitrobenzofuroxan with phenolates display excellent antimicrobial activity and have dual action, both against bacteria and fungi.

Hybrid compounds based on 4,6-dichloro-5-nitrobenzofuroxan, 7-chloro-4,6-dinitrobenzofuroxan, 5,7-dichloro-4,6-dinitrobenzofuroxan, and polyene antibiotics (amphotericin B and nystatin) have been prepared for the first time. They have exhibited biological activity comparable to that of starting antibiotics. Activity of the compound derived from 5,7-dichloro-4,6-dinitrobenzofuroxan and nystatin towards Trichophyton mentagrophytes is 4 times higher than that of nystatin.

New biologically active 2H-benzimidazole 1,3-dioxide derivatives, analogs of Sepin-1, have been synthesized starting from benzofuroxan. Electrophilic substitution of hydrogen in the 2H-benzimidazole ring occurs at different positions, depending on the electrophile nature.

Reaction of 6,8-dichloro-3,3-dimethyl-7-nitro-3H-2,1,4-benzoxadiazine 4-oxide with 4-aminomorpholine occurred through the benzoxadiazine ring opening to form 1,2-bis(2-amino-3,5-dichloro-4-nitrophenyl)-diazene oxide instead of the substitution product.

Synthesis of new organic compounds possessing biological activity is very challenging and is a current trend in medicinal chemistry. In recent studies benzofuroxan derivatives have been described as drugs active against bacteria and fungi, based on the ability of these compounds to induce intracellular release of nitric oxide (II). Consequently, many substances arising from reactions between(di)сhloro(di)nitrobenzofuroxans and different aliphatic, aromatic amines, amino acids, aminoalcohol nitrates, sulfanilamides, polyene antibiotics and other nucleophiles have been prepared. Novel 2H-benzimidazole 1,3-dioxides were also obtained by interaction of benzofuroxans with alcohols in sulfuric or perchloric acids. We also proposed a new method for the preparation of 2H-benzimidazole 1,3-dioxides by reaction of o-benzoquinonedioxime with ketones. Further nitration of the obtained compounds yielded a wide range of Sepin-1 analogues (separase inhibitors) with various substituents in the 2-position. Beside their high biological activity, 2H-benzimidazole 1,3-dioxides can be involved into thermal reactions. Heating of 2Н-benzimidazole 1,3-dioxides resulted in the formation of 3Н-[2,1,4]benzoxadiazine 4-oxides, which are unstable and easily transformed into initial 2H-benzimidazole 1,3-dioxides on exposure to sunlight. More prolonged heating of 3Н-[2,1,4]benzoxadiazine 4-oxides caused sequential elimination of the N-oxide oxygen atom to form 2H-benzimidazole mono N- oxides as final products of thermal reactions at moderate temperatures.

A series of novel hybrids based on benzofuroxan derivatives and fluoroquinolones (4a-d-6a-d) have been synthesized. Unexpectedly, the reactions have resulted in salt products formation during the hydrolysis of benzofuroxans by water molecules being present in the solvent instead of usual substitution products. All the compounds have been screened for antimicrobial and toxic activities. All resulting compounds retain high activity characteristic for fluoroquinolones. Many of the salts based on benzofuroxans and fluoroquinolones have higher activity than starting fluoroquinolones against Bacillus cereus 8035. Among the screened compounds, the compound 4d has shown the best antibacterial activity against B. cereus 8035, 8 times higher than the original Lomefloxacin (MBC value 1.5 μg/mL).

2H-Benzimidazole 1,3-dioxides undergo thermal isomerization to 3H-2,1,4-benzoxadiazine 4-oxides which are converted to 2H-benzimidazole 1-oxides on further heating. Irradiation of 3H-2,1,4-benzoxadiazine 4-oxides with sunlight induces their transformation to 2H-benzimidazole 1,3-dioxides. 3H-2,1,4-Benzoxadiazine 4-oxides containing nucleophilic heterocyclic substituents are considerably more stable to sunlight, and they can be used as photochromic compounds.