Novel Hybrid Compounds Containing Benzofuroxan and Aminothiazole Scaffolds: Synthesis and Evaluation of Their Anticancer Activity

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Тamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents.

Design of Novel 4-Aminobenzofuroxans and Evaluation of Their Antimicrobial and Anticancer Activity

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.

SYNTHESIS AND MASS SPECTROMETRIC CHARACTERISTICS OF 1-(AMINOARYL)BENZIMIDAZOLES

As a result of two-stage synthesis, a number of 1-(aminoaryl)benzimidazoles, potential biologically active substances, were obtained. During the first stage, an aromatic nucleophilic substitution reaction, 2-R-benzimidazoles reacted with halogen-nitroarenes. The process proceeded under mild conditions, this indicates a good nucleophilic properties of benzimidazole. It has been shown that during reduction, depending on the structure of 1-(nitroaryl)benzimidazoles in an acidic medium, in addition to the main process, acid-catalyzed isomerization can occur. Rearrangement was observed during the reduction of 1-(2-nitroaryl)benzimidazoles. The presence of a methyl group at the 2 position of the benzimidazole ring of these compounds hindered the rearrangement. When carrying out the reaction under conditions of heterogeneous catalysis in the reactor for flow hydrogenation, isomerization was also not observed. The use of 1-(4-nitroaryl)benzimidazoles as a substrate resulted in the formation of only one product. The mass spectral characteristics of 1-(aminoaryl)benzimidazoles were studied. The peak attribution of the molecular ion [M]+ was carried out by recording mass spectra with electrospray ionization. Ways of fragmentation of the molecular ion of these compounds under the influence of electron impact are proposed. Characteristic ions are identified. It was established that the fragmentation of the molecular ion of 1-(aminoaryl)benzimidazoles began either by elimination of the substituents, followed by cleavage of the two C—N bonds in imidazole, or by elimination of the HCN fragment of the imidazole ring and further elimination of the substituents. As a result, the formation of the cation radical of N-phenylbenzenediamine with m/z 181 was occurred. The fragmentation of this ion was carried out similarly to aromatic amines via elimination of a neutral HCN molecule. Further decay of alkylarylamine ions led to a group of characteristic fragmentation ions. Thus, mass spectrometry can be effectively used to identify N-aryl substituted benzimidazoles, as well as their decomposition products.

Dynamic Effects May Affect Hammett Linear Free Energy Relationship

The aromatic nucleophilic substitution reaction in the Clayden rearrangement reaction has an abnormal Hammett linear free energy relationship1. Inspired by the concertedstepwise variation of the aromatic nucleophilic substitution reaction in 20182, we determined the mechanism of Clayden rearrangement reaction under several conditions by DFT calculation then explained the mechanism diversity. We also found that there is a significant dynamic effect in the system due to the emergence of dynamic intermediates, which may be one of the reasons for the Hammett linear free energy relationship.

Dynamic Effects May Affect Hammett Linear Free Energy Relationship

The aromatic nucleophilic substitution reaction in the Clayden rearrangement reaction has an abnormal Hammett linear free energy relationship1. Inspired by the concertedstepwise variation of the aromatic nucleophilic substitution reaction in 20182, we determined the mechanism of Clayden rearrangement reaction under several conditions by DFT calculation then explained the mechanism diversity. We also found that there is a significant dynamic effect in the system due to the emergence of dynamic intermediates, which may be one of the reasons for the Hammett linear free energy relationship.

Direct synthesis of covalent triazine-based frameworks (CTFs) through aromatic nucleophilic substitution reactions

Triazine-based frameworks (CTFs) were synthesized through a new synthetic strategy in which C–C bonds were formed through aromatic nucleophilic substitution reaction.

A three-armed cryptand with triazine and pyridine units: synthesis, structure and complexation with polycyclic aromatic compounds

The aromatic nucleophilic substitution reaction based synthesis of a three-armed cryptand displaying 2,4,6-triphenyl-1,3,5-triazine units as caps and pyridine rings in the bridges, along with NMR, MS and molecular modelling-based structural analysis of this compound are reported. Appropriate NMR and molecular modelling investigations proved the formation of 1:1 host–guest assemblies between the investigated cryptand and some polynuclear aromatic hydrocarbons or their derivatives.

Facile aromatic nucleophilic substitution (SNAr) reactions in ionic liquids: an electrophile–nucleophile dual activation by [Omim]Br for the reaction

An aromatic nucleophilic substitution reaction in ionic liquids is promoted by an electrophile–nucleophile dual activation.

Azacalix[2]arene[2]carbazoles: synthesis, structure and properties

A new type of –NH– bridged azacalix[2]arene[2]carbazoles has been synthesized by aromatic nucleophilic substitution reactionviaone pot and/or fragment coupling strategy.