Synthesis of 7-amino-6-halogeno-3-phenylquinoxaline-2-carbonitrile 1,4-dioxides: a way forward for targeting hypoxia and drug resistance of cancer cells

Abstract

New water-soluble hypoxia activated 7-aminoquinoxaline 1,4-dioxides, prepared by the regioselective Beirut reaction, acted as HIF-1α suppressors and induced apoptosis in hypoxic and MDR cancer cells.

Synthesis and Characterization of Novel 2-Acyl-3-trifluoromethylquinoxaline 1,4-Dioxides as Potential Antimicrobial Agents

“…The comparison of the 13 C-NMR spectra of 2-propionyl-3trifluoromethylquinoxaline 1,4-dioxide (7d) and its amino derivatives 14a-c showed that the largest changes in the chemical shift of carbon atoms were observed at positions 3 and 10 of the quinoxaline nucleus due to the conjugation with the amino group. The observed changes corresponded to the increments (I C ) of the tertiary amino group in the 13 C-NMR spectra of arenes [29,34] and well correlated to the data for previously described amino derivatives of quinoxaline 1,4-dioxides [21,31] (Supplementary Material, Figures S5-S54; Table S1). The structure of the obtained derivatives 14b-c revealed that the halogen atoms at positions 6 and 7 of the starting compounds 5-11b-c differed in the reactivity for the nucleophilic substitution.…”

“…Thus, piperazine moiety has important role in antimicrobial properties of fluoroquinolone antibiotics such as Ciprofloxacin and their analogues. This cyclic diamine and its derivatives were efficiently used as the N-nucleophiles for the diversification of the quinoxaline scaffolds and preparation of water-soluble derivatives with promising anticancer potencies [21,31]. However, attempts to carry out the nucleophilic substitution of the halogen atom on the quinoxaline core of 5-11a-c by piperazine in DMF as described earlier [21] were ineffective due to the formation of a mixture of deoxygenated analogs as the main products of the reaction.…”

“…The observed highest reactivity of the fluorine atom at position 6 of quinoxaline 1,4-dioxide 15-18b in comparison to congeners 12-14b in the substitution reaction could be explained by the biggest electron-withdrawing effect of the aroyl groups at position 2 of the quinoxaline ring of these derivatives. We have earlier developed an original scheme for the synthesis of 7-aminoquinoxaline-2-carbonitrile 1,4-dioxides based on the Beirut reaction of 5-aminosubstituted benzofuroxans and benzoylacetonitrile, which proceeded with a good regioselectivity [31]. Considering this data, we tested the possibilities of this approach for the synthesis of congeners with 3-trifluoromethyl group, so a tentative heterocyclization of the previously described 5-(Boc-piperazin-1-yl)-6-chlorobenzofuroxan 19 [31] with 1,1,1-trifluorohexane-2,4-dione in THF in the presence of the triethylamine led to a formation of the derivative of quinoxaline 1,4-dioxide in a good yield (Scheme 3).…”

“…We have earlier developed an original scheme for the synthesis of 7-aminoquinoxaline-2-carbonitrile 1,4-dioxides based on the Beirut reaction of 5-aminosubstituted benzofuroxans and benzoylacetonitrile, which proceeded with a good regioselectivity [31]. Considering this data, we tested the possibilities of this approach for the synthesis of congeners with 3-trifluoromethyl group, so a tentative heterocyclization of the previously described 5-(Boc-piperazin-1-yl)-6-chlorobenzofuroxan 19 [31] with 1,1,1-trifluorohexane-2,4-dione in THF in the presence of the triethylamine led to a formation of the derivative of quinoxaline 1,4-dioxide in a good yield (Scheme 3). The obtained by this scheme compound had physicochemical and spectral characteristics identical to derivative 14c, synthesized by the nucleophilic substitution of the chlorine atom of quinoxaline 1,4-dioxide 7с (Scheme 2).…”

Novel Derivatives of Quinoxaline-2-carboxylic Acid 1,4-Dioxides as Antimycobacterial Agents: Mechanistic Studies and Therapeutic Potential

“…The revealed regioselectivity of the nucleophilic substitution of the chlorine atom at position 6 of quinoxalines 2 and 3 (Scheme 1) can be explained by the conjugation of the C6 carbon atom with the electron-withdrawing group at position 2 of the heterocycle of these derivatives. This conjugation leads to an increase in the positive charge at C6 carbon atom as well as stabilization of the intermediate Meisenheimer complex, thereby enhancing its reactivity in nucleophilic substitution reactions [13]. The structure of all synthesized compounds 4-7 (Scheme 1) was characterized by using HRMS ESI, HPLC, and NMR spectroscopies.…”