Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection

Our
team had previously identified certain indolecarboxamides that
represented a new chemical scaffold that showed promising anti-TB
activity at both an in vitro and in vivo 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-N-((1R,2R,3R,5S)-2,6,6-trimethylbicyclo­[3.1.1]­heptan-3-yl)-1H-indole-2-carboxamide (26), that shows excellent
activity against drug-sensitive (MIC = 0.012 μM; SI ≥
16000), multidrug-resistant (MDR), and extensively drug-resistant
(XDR) Mycobacterium tuberculosis strains, has superior
ADMET properties, and shows excellent activity in the TB aerosol lung
infection model. Compound 26 is also shown to work in
synergy with rifampin. Because of these properties, we believe that
indolecarboxamide 26 is a possible candidate for advancement
to human clinical trials.