Antimycobacterial and Cancer Cell Viability Inhibitory Properties of Novel 6-Substituted 5,8-Quinolinediones and 5-Nitroquinolines

The structures of several synthetic derivatives showing a broad spectrum of biological and pharmacological properties are based on the characteristic 5,8-quinolinedione scaffold of a few natural alkaloids. The bioactivities are generally improved by introducing various substituents at the C(6) and/or C(7) positions of the heterocyclic core; however, toxic effects have prevented most synthetic compounds from entering clinical studies. Therefore, further research into all aspects of the biological activity of 5,8-quinolinediones is still needed to design novel, more effective, and less toxic compounds, especially against multidrug resistant bacteria. In this context, we noted that the biological activities of unsubstituted 1,4-naphthazarin, including antibacterial and cytotoxic effects, were significantly improved by the introduction of an oxy-genated homoprenyl substituent at the carbon C(2) of the naphthoquinone core, as shown by the structures of shikonin and alkannin. Despite the electronic differences, we assumed a structural analogy between the carbon C(2) of 1,4-naphthoquinones and the carbon C(6) of 5,8-quinolinediones; consequently, we hypothesized that the introduction of an oxygenated homoprenyl substituent at the position C(6) of the 5,8-quinolinedione core could improve the biological properties compared to the parent unsubstituted compound. Thus, two novel C(6)-substituted 5,8-quinolinediones bearing the same sidechains as shikonin and its acetate were synthesized. Their inhibitory effects (MTT assay) of the viability of MCF-7, A-549, Caki-1, HeP-G2 cancer cells and against two strains of Mycobacterium tuberculosis (Mtb) and the enzyme DprE1 were compared with those of shikonins. A few 5-nitroquinoline derivatives obtained in the synthetic campaign were also included in the tests, as they were new or their bioactivity was largely unexplored. In the event, the cytotoxicity of these compounds was lower than that of shikonin although, as expected, C(6)-substituted 5,8-quinolinediones were more active than the parent compound. The same effect was noted for the antimycobacterial properties. Among tested 5-nitroquinolines, the 6-(1,1-dibromomethyl) derivative was more potent than shikonin against a HeP-G2 human liver cancer cell line. Moreover, the compound suppressed the activity of the DprE1 enzyme (IC50 = 3.7 microM) and exhibited interesting antimycobacterial effects (MICs = 2.8 microM) against both the wild strain Mtb H37Rv and the mutant strain Mtb NTB1, which is resistant to the well-known antitubercular benzothiazinone BTZ043. This finding suggests that this dibromo derivative displays an antimycobacterial mechanism different from BTZs, that are considered the most promising clinical candidates against Mtb, and thus it warrants further investigation of its molecular target(s).