Abstract
A variety of 2,3-bifunctionalized quinoxalines (6-14) have been prepared by the condensation of 1,6-disubstituted-hexan-1,3,4,6-tetraones (1-4) with o-phenylenediamine, (R,R)-1,2-diaminocyclohexane and p-nitro-o-phenylenediamine. It is concluded that strong intramolecular N-H----O bonds in the favoured keto-enamine form may be responsible for the minimal biological activities observed in DNA footprinting, anti-tubercular, anti-fungal and anticancer tests with these hyper π-conjugated quinoxaline derivatives. However, subtle alteration by addition of a nitro group affecting the charge distribution confers significant improvements in biological effects and binding to DNA.
Highlights
In recent years, polyfunctionalised quinoxalines have been prepared and studied because of their interesting biological activities [1,2,3,4,5] and DNA interactive behaviour [6,7,8]
We describe our efforts to extend the methodology to the synthesis of pharmacologically important quinoxalines bearing functional groups at positions 2 and 3 of the quinoxaline ring
We postulate that the strong tendency to form an intramolecular N-H----O bond in the predominant form is likely to be responsible for the lack of biological activity observed with these hyper π-conjugated quinoxaline derivatives
Summary
In recent years, polyfunctionalised quinoxalines have been prepared and studied because of their interesting biological activities [1,2,3,4,5] and DNA interactive behaviour [6,7,8]. Performed 1H-, 13C- and 15N-NMR studies have shown that symmetrically substituted quinoxaline ligands 6, 7 and 10 containing phenyl or cyclohexyl rings lead predominantly to a ketoenamine form with N-H---O intramolecular hydrogen bonds [16]. The existence of this preferred tautomeric form was confirmed by X-ray structural studies of 6 and 10. The modulation of the conjugation pathway has been studied by replacing either the external phenyl group with a neo-pentyl group or a propyl group, or the central aromatic portion with a cyclohexyl moiety The effects of these substitutions on possible anti-tumour activity and interaction with DNA are reported. The development of a short and convergent approach to the synthesis allows us easy access to the new quinoxaline family 6-14
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