Water-Soluble Salts Based on Benzofuroxan Derivatives-Synthesis and Biological Activity.

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.

The Reactivity of Azidonitrobenzofuroxans towards 1,3-Dicarbonyl Compounds: Unexpected Formation of Amino Derivative via the Regitz Diazo Transfer and Tautomerism Study.

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.

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 Tamoxifen. 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.