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

Pankaj Bhattarai, Pooja Hegde, Wei Li, Pavan Kumar Prathipati, Casey M. Stevens, Lixinhao Yang, Hinman Zhou, Amit Pandya, Katie Cunningham, Jenny Grissom, Mariaelena Roman Sotelo, Melanie Sowards, Lilian Calisto, Christopher J. Destache, Sonia Rocha-Sanchez, James C. Gumbart, Helen I. Zgurskaya, Mary Jackson, E. Jeffrey North

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)170-187
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number1
StatePublished - Jan 12 2023

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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