Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in
developing countries. Non-tuberculous mycobacteria (NTM) infections
are rising and prey upon patients with structural lung diseases such
as chronic obstructive pulmonary disease (COPD) and cystic fibrosis.
All mycobacterial infections require lengthy treatment regimens with
undesirable side effects. Therefore, new antimycobacterial compounds
with novel mechanisms of action are urgently needed. Published indole-2-carboxamides
(IC) with suggested inhibition of the essential transporter MmpL3
showed good potency against whole-cell M.tb, yet
had poor aqueous solubility. This project focused on retaining the
required MmpL3 inhibitory pharmacophore and increasing the molecular
heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole,
mandelic acid, imidazole, and acetamide functional groups coupled
to lipophilic head groups, where lead acetamide-based compounds maintained
high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs,
were non-cytotoxic, and were determined to be MmpL3 inhibitors.