Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection StecJozef OnajoleOluseye K. LunShichun GuoHaidan MerenbloomBenjamin VistoliGiulio BishaiWilliam R. KozikowskiAlan P. 2016 Our team had previously identified certain indolecarboxamides that represented a new chemical scaffold that showed promising anti-TB activity at both an <i>in vitro</i> and <i>in vivo</i> level. Based on mutational analysis using bacteria found resistant to one of these indolecarboxamides, we identified the trehalose monomycolate transporter MmpL3 as the likely target of these compounds. In the present work, we now further elaborate on the SAR of these compounds, which has led in turn to the identification of a new analog, 4,6-difluoro-<i>N</i>-((1<i>R</i>,2<i>R</i>,3<i>R</i>,5<i>S</i>)-2,6,6-trimethylbicyclo­[3.1.1]­heptan-3-yl)-1<i>H</i>-indole-2-carboxamide (<b>26</b>), that shows excellent activity against drug-sensitive (MIC = 0.012 μM; SI ≥ 16000), multidrug-resistant (MDR), and extensively drug-resistant (XDR) <i>Mycobacterium tuberculosis</i> strains, has superior ADMET properties, and shows excellent activity in the TB aerosol lung infection model. Compound <b>26</b> is also shown to work in synergy with rifampin. Because of these properties, we believe that indolecarboxamide <b>26</b> is a possible candidate for advancement to human clinical trials.