Diaryl-Aminoindazole with Extensive In Vitro Mycobactericidal Activity Dependent on Exposure to Reactive Nitrogen Species

A bromoindazole was reported with the ability to rapidly and extensively kill <i>Mycobacterium tuberculosis</i> (Mtb) in vitro, but only in the presence of sublethal levels of reactive nitrogen species (RNS) (Warrier et al., ACS Infectious Diseases 1:585-560, 2015). After learning that that compound was poorly tolerated in mice, we identified a diaryl-aminoindazole with even more pronounced ability to kill Mtb in vitro in an RNS-dependent manner, along with RNS-dependent mycobactericidal activity against <i>Mycobacterium avium</i> and RNS-dependent mycobacteristatic activity against <i>Mycobacterium abscessus</i>. The compound was orally bioavailable and well tolerated in mice. However, 4- to 8-week treatment of mice with the diaryl-aminoindazole did not reduce their pulmonary burden of Mtb. Possible explanations include the low levels of compound detected in plasma at trough and the low levels of RNS detected in the lungs of these mice.

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Publication Details

Journal
ACS Infectious Diseases
Published
2026-01-06
DOI
https://doi.org/10.1021/acsinfecdis.5c00879
Primary Topic
Tuberculosis Research and Epidemiology
Type
article
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article

Diaryl-Aminoindazole with Extensive In Vitro Mycobactericidal Activity Dependent on Exposure to Reactive Nitrogen Species

Carl Nathan, Gregory T. Robertson, Veronique Anne Dartois, María Martínez-Hoyos et al.
ACS Infectious Diseases
Tuberculosis Research and Epidemiology
article

Diaryl-Aminoindazole with Extensive In Vitro Mycobactericidal Activity Dependent on Exposure to Reactive Nitrogen Species

Carl Nathan, Gregory T. Robertson, Veronique Anne Dartois, María Martínez-Hoyos, Thulasi Warrier, K L Li, Alfonso Mendoza-Losana, Anne J. Lenaerts, Brendan Prideaux, Shashirekha Mundhra, Isabelle Bonnet, Xiuju Jiang, Veronica Gruppo, Esther Porras de Francisco, Jeffrey Aubé
article en

Abstract

A bromoindazole was reported with the ability to rapidly and extensively kill <i>Mycobacterium tuberculosis</i> (Mtb) in vitro, but only in the presence of sublethal levels of reactive nitrogen species (RNS) (Warrier et al., ACS Infectious Diseases 1:585-560, 2015). After learning that that compound was poorly tolerated in mice, we identified a diaryl-aminoindazole with even more pronounced ability to kill Mtb in vitro in an RNS-dependent manner, along with RNS-dependent mycobactericidal activity against <i>Mycobacterium avium</i> and RNS-dependent mycobacteristatic activity against <i>Mycobacterium abscessus</i>. The compound was orally bioavailable and well tolerated in mice. However, 4- to 8-week treatment of mice with the diaryl-aminoindazole did not reduce their pulmonary burden of Mtb. Possible explanations include the low levels of compound detected in plasma at trough and the low levels of RNS detected in the lungs of these mice.

ACS Infectious DiseasesVol. 12(2)
University of North Carolina at Chapel Hill (US), Cornell University (US), GlaxoSmithKline (France) (FR), Hackensack Meridian Health (US), GlaxoSmithKline (Spain) (ES), Center for Discovery (US), Weill Cornell Medicine (US), Universidad Carlos III de Madrid (ES), Colorado State University (US)
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Tuberculosis Research and Epidemiology
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