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

Abstract

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.

Recent Advances in the Synthesis and Biomedical Applications of Heterocyclic NO-Donors

“…Using a super-electrophilic nature of the benzofuroxan ring system, a series of promising anticancer drug candidates 65 bearing 2-aminothiazole moiety was synthesized ( Scheme 33 ). The cytotoxic activity of the lead benzofuroxan derivative bearing 4-methoxyphenyl substituent at the aliphatic nitrogen atom was attributed to induction of apoptosis in m-HeLa cells at early stages (10.7–17.3% of apoptotic cells were observed using 50–100 μM concentrations) [ 110 ].…”

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

“…]oxadiazole 1-oxide (benzofuroxan) have attracted the attention of chemists due to the biological activity exhibited by this class of heterocycle. Benzofuroxans have been proposed as monoamine oxidase inhibitors [1,2] and calcium channel modulators [3,4], and possess vasodilating and cardiotropic [5], antitumor [6][7][8][9], antiparasitic [10,11], anti-tuberculosis [12][13][14], bactericidal [15][16][17], virucidal, sporicidal, and fungicidal activities [18,19]. Moreover, benzofuroxans exhibit anunusual chemical behavior due to the specificity of the electronic structure of the 1,2,5-oxadiazole-N-oxide cycle.…”

DFT Quantum-Chemical Calculation of Thermodynamic Parameters and DSC Measurement of Thermostability of Novel Benzofuroxan Derivatives Containing Triazidoisobutyl Fragments

“…To obtain such compounds, we selected 5,7-dichloro-4,6-dinitro-and 7-chloro-4,6-dinitrobenzofuroxans containing one or two chlorine atoms in their structures, which can be easily replaced by triazidoisobutyl fragments. 5,7-dichloro-4,6-dinitro-and 7-chloro-4,6-dinitrobenzofuroxans are convenient platforms for their further modification in order to obtain new derivatives containing various functional groups [20][21][22][23][24][25]. In this paper, we discovered new benzofuroxan derivatives containing triazidoisobutyl fragments, studies of temperature characteristics, assessment of compatibility with cellulose nitrates and quantum-chemical calculations of the thermodynamic and explosive characteristics of the obtained compounds.…”