Anthranilic amide and imidazobenzothiadiazole compounds disrupt <i>Mycobacterium tuberculosis</i> membrane potential.
Smith J, Wescott H, Early J, Mullen S, Guzman J, Odingo J, Lamar J, Parish T.
A family of compounds typified by an anthranilic amide <b>1</b> was identified from a whole-cell screening effort targeted at identifying compounds that disrupt pH homeostasis in <i>Mycobacterium tuberculosis</i>. <b>1</b> demonstrated bactericidal activity against non-replicating <i>M. tuberculosis</i> in pH 4.5 buffer (MBC<sub>4.5</sub> = 6.3 μM). Exploration of the structure-activity relations failed to simplify the scaffold. The antitubercular activity proved dependent on the lipophilicity and planarity of the molecule and directly correlated with mammalian cytotoxicity. Further studies revealed a pH-dependent correlation between the family's disruption of <i>M. tuberculosis</i> membrane potential and antitubercular activity, with active compounds causing a drop in membrane potential at concentrations below their MBC<sub>4.5</sub>. A second compound family, identified in the same screening effort and typified by imidazo(4,5-<i>e</i>)(2,1,3)benzothiadiazole <b>2</b>, provided a contrasting profile. As with <b>1</b>, structure-activity profiling of <b>2</b> (MBC<sub>4.5</sub> = 25 μM) failed to minimize the initial scaffold, mammalian cytotoxicity was observed for a majority of the active compounds, and many of the active compounds disrupted <i>M. tuberculosis</i> membrane potential. However, unlike the anthranilic amide compounds, the benzothiadiazole compounds disrupted <i>M. tuberculosis</i> membrane potential primarily at concentrations above the MBC<sub>4.5</sub> in a pH-independent fashion. These differences suggest an alternative mechanism of action for the benzothiadiazole compounds. As a result, while the cytotoxicity of the anthranilic amides limits their utility to tool compounds, benzothiadiazole <b>2</b> presents an attractive target for more focused SAR exploration.