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

Jozef Stec, Oluseye K. Onajole, Shichun Lun, Haidan Guo, Benjamin Merenbloom, Giulio Vistoli, William Ramses Bishai, Alan P. Kozikowski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6232-6247
Number of pages16
JournalJournal of Medicinal Chemistry
Volume59
Issue number13
DOIs
StatePublished - Jul 14 2016

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Tuberculosis
Animal Models
Rifampin
Infection
Aerosols
Mycobacterium tuberculosis
Pharmaceutical Preparations
Clinical Trials
Bacteria
Lung
indole
trehalose monomycolate
3-(5-nitrofuryl)-7-(5-nitrofurfurylidene)-3,3a,4,5,6,7-hexahydro-2H-indazole
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection. / Stec, Jozef; Onajole, Oluseye K.; Lun, Shichun; Guo, Haidan; Merenbloom, Benjamin; Vistoli, Giulio; Bishai, William Ramses; Kozikowski, Alan P.

In: Journal of Medicinal Chemistry, Vol. 59, No. 13, 14.07.2016, p. 6232-6247.

Research output: Contribution to journalArticle

Stec, Jozef ; Onajole, Oluseye K. ; Lun, Shichun ; Guo, Haidan ; Merenbloom, Benjamin ; Vistoli, Giulio ; Bishai, William Ramses ; Kozikowski, Alan P. / Indole-2-carboxamide-based MmpL3 Inhibitors Show Exceptional Antitubercular Activity in an Animal Model of Tuberculosis Infection. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 13. pp. 6232-6247.
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