In light of the great importance of quinoxalinederivatives,in recent years efforts have been made indeveloping new methodologies for the synthesis of thesecompounds .
We haverecently demonstrated that polyvinylpolypyrrolidoniume triflateefficiently catalyzed reaction between indole and aldehydes for thepreparation of bis-indolyl methane derivatives .
Katritzky AR, Rees CW. One-pot three-component synthesis of quinoxaline and phenazine ring systems using Fischer carbine complexes. Comprehensive Heterocyclic Chemistry, Pergamon Oxford Part 2B 1984;3:157-65.
Orthophenylenediamine, phosphrousoxytrichloride, oxalic acid dimethylsulfoxide(DMSO), 4 amino acetophenone, dimethylformamide(DMF), hydrochloric acid, chloroform, hexane, ethanol were used for the synthesis of quinoxalines. The following experimental methods were used for the characterization of the synthesized compounds. Melting points of the synthesized compounds were determined in open capillary tubes and are uncorrected. The IR spectrum was recorded on ELICIO FTIR spectrometer using potassium bromide pellets. 1H-NMR spectra of the compounds in deutiriated dimethylsulfoxide was recorded on BRUKER Av 400 MHz spectrometer. Mass spectrum was recorded on GCMS QP 5000 shimadzu. Thin layer chromatography was performed using precoated aluminium plates coated with silica gel GF254 [E. Merck]. N-hexane: ethyl acetate was used as the eluent. The spots were visualized in the ultraviolet light chamber.
Kumar A, Verma A, Chawla G. Vaishali. Synthesis, Anti-inflammatory and antimicrobial activities of new hydrazone and quinoxaline derivatives. Int J Chem Tech Res 2009;1(4):1177-81.
In this paper, we synthesized quinoxaline derivatives with bis(fluoromethyl), bis(chloromethyl), and bis(iodomethyl) units at the 2- and 3-positions, as well as various substituents at the 6- and/or 7-positions (). Their antibacterial and antifungal activities were evaluated by means of minimum inhibitory concentration assays, and relationships between the substituents and the antimicrobial activities were studied.
The 2,3-bis(fluoromethyl)quinoxalines 2a–8a were synthesized by the reaction of the corresponding bromomethyl compounds 2c–8c with potassium fluoride in the presence of 18-crown-6 in acetone, giving 18–84% yields) (). The fluorination of quinoxaline derivatives bearing a strong electron-withdrawing group at the 6-position, such as 2c–4c, gave many by-products and so the yields of the target compounds were low. In particular, the fluorination of 1c (6-NO2) afforded a complex mixture from which 1a could not be extracted.)
The 2,3-bis(iodomethyl)quinoxalines 2d–8d were synthesized from 2c–8c by the Finkelstein reaction,,) and obtained in 36–94% yields (). These reactions were also monitored with HPLC. As with some of the fluorination reactions, the reactions of 2d and 3d, which had the strong electron-withdrawing substituents CN and CF3 respectively at the 6-position, were accompanied by many side reactions, resulting in low yields for the target compounds, and the iodination of 1c having a nitro group at the 6-position did not afford 1d at all.)
The antibacterial activities of the newly-synthesized quinoxaline derivatives (2a–8a, 1b–8b, 2d–8d), as well as those of previously reported compounds (1c–8c),) were evaluated by means of minimum inhibitory concentration (MIC) assays; the results are summarized in . All compounds were inactive against Gram-negative bacteria. The outer membrane of Gram-negative bacteria is covered by many lipopolysaccharides, which consist mainly of hydrophilic polysaccharides.) Therefore, the lipophilic materials are hard to reach the surface of the outer membrane. We think that the synthesized 2,3-bis(halomethyl)quinoxaline derivatives are too lipophilic to come close to the outer membrane of Gram-negative bacteria.
For Gram-positive bacteria, while 2,3-bis(fluoromethyl)quinoxalines 2a–8a exhibited no antibacterial activity, four 2,3-bis(chloromethyl)quinoxalines (1b–3b, 8b), five 2,3-bis(iodomethyl)quinoxalines (2d, 4d–6d, 8d), and all eight 2,3-bis(bromomethyl)quinoxalines (1c–8c) did. Among them, 2,3-bis(chloromethyl)-6-nitroquinoxaline (1b) showed the highest activity. The relationships between the substituents and the activities of quinoxaline derivatives suggest that the electrophilicity of halomethyl groups plays an important role in their antibacterial activity. That is, the lower electrophilicity of the fluoromethyl group compared with the other halomethyl groups can be interpreted as directly responsible for the inactivity of 2,3-bis(fluoromethyl) derivatives.
Nitrogen-containing heterocycles form the main component of many essential biomolecules, from DNA and RNA to coenzymes. They are thought to have high biocompatibility, and have been used as structural units within many pharmaceutical products.) Among the various classes of heterocyclic units, the quinoxaline ring is one of the components involved in a variety of antibiotic molecules such as hinomycin, levomycin, and actinoleutin.–) Furthermore, many quinoxaline derivatives have been reported to possess anticancer, antibacterial, antifungal, antiviral, and antiprotozoal activities.–)
When the activities of the quinoxaline derivatives with 6-CN (2b, 2c, 2d) and 6-Cl (5b, 5c, 5d) substituents were compared, we found the halomethyl groups exhibited high activity in the descending order –CH2I>–CH2Br>–CH2Cl. A similar trend (–CH2I≈–CH2Br>–CH2Cl) was observed in compounds containing 6-F (4b, 4c, 4d), 6-Br (6b, 6c, 6d), and 6-OCH3 (8b, 8c, 8d) substituents. In these cases, the compounds that exhibited the highest activity possessed iodomethyl, the halomethyl group of highest electrophilicity. In contrast, the activities of 6-CF3-substituted quinoxalines (3b, 3c, 3d) ranked as 3c (–CH2Br)>3b (–CH2Cl), with 2,3-bis(iodomethyl)quinoxaline (3d) being completely inactive. These results seem to be caused by heightened electrophilicity as well, although in this case it becomes excessive: the electron-withdrawing trifluoromethyl group at the 6-position of 3d increases the electrophilicity of the iodomethyl group so much that 3d undergoes decomposition under the MIC assay conditions before it can exert its antibacterial activity. A similar relationship between electron-withdrawing substituents at the 6-position and antibacterial activity was also observed in the case of 6-NO2 substituted quinoxalines (1b, 1c), whose activity became the highest when the substituents at the 2- and 3-positions were chloromethyl, a less reactive substituent than bromomethyl. As with the 6-CF3-substituted quinoxalines, the strong electron-withdrawing nitro group at the 6-position increases the electrophilicity of halomethyl groups, which would result in adequate reactivity for the chloromethyl group of 1b, but extend too far and induce instability for the bromomethyl group of 1c. The notion of electron-withdrawing group-induced destabilization of halomethyl groups seems to also be supported by the fact that the reaction of 2,3-bis(bromomethyl)-6-nitroquinoxaline 1c with sodium iodide afforded complex mixtures of by-products, instead of forming the desired iodinated compounds.