Novel 3-Aminothieno[2,3- b]pyridine-2-carboxamides with Activity against Mycobacterium tuberculosis

  • ACS Med Chem Lett. 2025 Jan 3;16(2):241-249. doi: 10.1021/acsmedchemlett.4c00472.
Brock E Lynde  1 ,  Danielle M Chemaly  1 ,  Vanessa Pietrowski Baldin  1 ,  Eric Greve  1 ,  Christopher L Harding  1 ,  Jasmin M Graner  1 ,  Mason Hardy  1 ,  Sultan Chowdhury  1 ,  Tanya Parish  1  2
Affiliations
  • 1. Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98109, United States.
  • 2. Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington 98195, United States.
PMID: 39967629 DOI: 10.1021/acsmedchemlett.4c00472
Abstract

We conducted an exploration of the 3-aminothieno[2,3-b]pyridine-2-carboxamide (TPA) series for its potential as a drug scaffold against Mycobacterium Tuberculosis. Existing analogs were active against a Recombinant strain of M. Tuberculosis with reduced expression of the sole signal peptidase LepB, but with poor activity against the wild-type strain. Our aim was to improve potency and explore the structure-activity relationship of the series. We identified two subsets of TPA. The first subset of compounds had equipotent activity against wild-type and LepB hypomorph strains and may represent a series with a different target. The second subset of compounds had increased activity against the LepB hypomorph strain and thus appears to be pathway-specific. Among this latter set we identified 17af as a potent inhibitor (IC90 = 1.2 μM) with some cytotoxicity (IC50 = 19 μM) and which retained increased activity against the LepB hypomorph (IC90 = 0.41 μM).

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