Pyrroloquinolone-Based Compounds as a Novel Antimycobacterial Chemotype

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains the world's most lethal infectious disease, posing an uncontained health challenge. The major hurdles are the long treatments and low patient compliance that leads to the appearance of resistance, as well as the lack of drugs that effectively tackle the latent infections. Herein we report the development of compounds with the ability to target the electron transport chain of Mtb by inhibiting cytochrome <i>bcc</i> (cyt-<i>bcc</i>) (<b>7a</b>-<b>i</b>) and additionally being capable of inhibiting cytochrome <i>bd</i> (cyt-<i>bd</i>) (<b>7j</b> and <b>7k</b>). We present the synthesis, determination of physicochemical properties, evaluation of the antibacterial activity, and cytotoxicity assessment of pyrroloquinolone-based compounds. The antibacterial evaluation of <b>7a</b>-<b>k</b> showed selectivity toward mycobacteria, and the results identify cyt-<i>bcc</i> as their target. Compounds <b>7j</b> and <b>7k</b> presented promising results against Mtb and good physicochemical properties. Cytotoxicity assays revealed a good safety profile regarding the toxicity for human cell lines.