New heterocyclic scaffolds by intramolecular reactions of 4-quinolone-2-carboxamides

The quinolone moiety is an important structural unit in medicinal chemistry and many compounds with this scaffold have shown a broad range of biological properties including anticancer, antimicrobial, antiviral and antimalarial activity. In pursuance of our research on the development of new antitumor compounds, we became interested in accessing structurally diverse heterocyclic rings containingthe quinolone moiety.We have devised a reliable synthetic route to 4-quinolone-based fused systems starting from 4-quinolone-2-carboxylic acid oxoamides. The acid-catalyzed intramolecular reaction of N-unsubstituted quinolones gives structurally diverse compounds, depending on the length of the chain. Acid treatment of β-oxoamides furnishes 3H-pyrazino[1,2-a]quinoline-4,6-diones, due to the nucleophilic attack of N-1 to the carbonyl group, whereas acid treatment of δ- and ε-oxoamides leads to the formation of tetracyclic compounds by a tandem heteroannulation reaction. As no examples of such heterocyclic structures have been reported in the literature so far, the sequence represents a versatile approach to new scaffolds andspecifically provides a method for the rapid preparation of differently substituted derivatives. The results of a preliminary test on compound 2 (m = 1) (IC50 = 10 μM on H460 tumor cell lines) suggest that these classes of compounds could be worth of further investigation.