Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity

Nicholas D. Franz, Juan Manuel Belardinelli, Michael A. Kaminski, Louis C. Dunn, Vinicius Calado Nogueira de Moura, Michael A. Blaha, Dan D. Truong, Wei Li, Mary Jackson, E. Jeffrey North

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics.

Original languageEnglish (US)
Pages (from-to)3746-3755
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume25
Issue number14
DOIs
StatePublished - Jul 15 2017

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Mycobacterium
Smegma
Mycolic Acids
Anti-Bacterial Agents
Cytotoxicity
Mycobacterium tuberculosis
Tuberculosis
Therapeutics
Cells
Cell Line
Testing
Pharmaceutical Preparations
indole

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Franz, N. D., Belardinelli, J. M., Kaminski, M. A., Dunn, L. C., Calado Nogueira de Moura, V., Blaha, M. A., ... North, E. J. (2017). Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity. Bioorganic and Medicinal Chemistry, 25(14), 3746-3755. https://doi.org/10.1016/j.bmc.2017.05.015

Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity. / Franz, Nicholas D.; Belardinelli, Juan Manuel; Kaminski, Michael A.; Dunn, Louis C.; Calado Nogueira de Moura, Vinicius; Blaha, Michael A.; Truong, Dan D.; Li, Wei; Jackson, Mary; North, E. Jeffrey.

In: Bioorganic and Medicinal Chemistry, Vol. 25, No. 14, 15.07.2017, p. 3746-3755.

Research output: Contribution to journalArticle

Franz, ND, Belardinelli, JM, Kaminski, MA, Dunn, LC, Calado Nogueira de Moura, V, Blaha, MA, Truong, DD, Li, W, Jackson, M & North, EJ 2017, 'Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity', Bioorganic and Medicinal Chemistry, vol. 25, no. 14, pp. 3746-3755. https://doi.org/10.1016/j.bmc.2017.05.015
Franz ND, Belardinelli JM, Kaminski MA, Dunn LC, Calado Nogueira de Moura V, Blaha MA et al. Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity. Bioorganic and Medicinal Chemistry. 2017 Jul 15;25(14):3746-3755. https://doi.org/10.1016/j.bmc.2017.05.015
Franz, Nicholas D. ; Belardinelli, Juan Manuel ; Kaminski, Michael A. ; Dunn, Louis C. ; Calado Nogueira de Moura, Vinicius ; Blaha, Michael A. ; Truong, Dan D. ; Li, Wei ; Jackson, Mary ; North, E. Jeffrey. / Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity. In: Bioorganic and Medicinal Chemistry. 2017 ; Vol. 25, No. 14. pp. 3746-3755.
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