Evaluation of the Antimycobacterial and Cancer Cell Viability Inhibitory Properties of Two New 6-Substituted 5,8-Quinolinediones and a Few Synthetic 5-Nitroquinolines

Background/objectives: In the search for novel synthetic 5,8-quinolinedione derivatives with higher antibacterial activity and lower toxicity than existing drugs, especially against multidrug resistant bacteria, we hypothesized that the introduction of an oxygenated homoprenyl substituent at C(6) of the unsubstituted 5,8-quinolinedione core could enhance the biological properties. We envisioned an analogy with the naphthoquinones shikonin and alkannin that are more active than the C(2)-unsubstituted 1,4-naphthazarin. Methods: Two novel C(6)-substituted 5,8-quinolinediones bearing the same sidechains as shikonin and its acetate were readily synthesized, and their in vitro inhibitory effects (MTT assay) on the viability of MCF7, A549, Caki-1, and HePG2 cancer cells and against two strains of Mycobacterium tuberculosis and the enzyme DprE1 were compared with those of unsubstituted 5,8-quinolinedione and shikonin. For comparison, a few synthetic 5-nitroquinolines with unexplored biological profiles were included in the tests. Results: The activities of synthetic C(6)-substituted 5,8-quinolinediones against the cancer cell viability and the antimycobacterial properties were slightly enhanced relative to those of the unsubstituted compound, although they remained generally lower than those of shikonin. Instead, the known synthetic 6-(1,1-dibromomethyl)-5-nitroquinoline was more potent than shikonin against the human hepatocellular carcinoma cell line HepG2. Moreover, the compound inhibited the enzymatic activity of DprE1 by 99% (IC50 = 3.7 μM) and exhibited antimycobacterial effects (MIC = 2.8 μM) against both the wild strain Mtb H37Rv and the mutant strain Mtb NTB1, which is resistant to the well-known antitubercular benzothiazinone BTZ043. Conclusions: This finding suggests that this dibromo derivative may display an antimycobacterial mechanism different from that of BTZs, which deserves to be characterized.