A Series of Pyrazolo-Quinazoline Amines Inhibits the Cytochrome bd Oxidase in Mycobacterium tuberculosis

  • J Med Chem. 2026 Feb 12;69(3):2130-2144. doi: 10.1021/acs.jmedchem.5c01616.
Samsher Singh  1 ,  Pearly Shuyi Ng  2 ,  Umayal Lakshmanan  2 ,  Vikneswaran Mathiyazakan  1  3 ,  Thomas Wiggins  4 ,  Bei Shi Lee  1  4 ,  Shi Hua Ang  2 ,  Sandra Wei Lin Sim  2 ,  May Delos Santos  5 ,  Garrett Moraski  6 ,  Marvin Miller  7 ,  Michael Berney  4  8 ,  Gerhard Grüber  3 ,  Kevin Pethe  1  9  10  11
Affiliations
  • 1. Nanyang Technological University, Lee Kong Chian School of Medicine, Singapore 636921, Singapore.
  • 2. Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore 138670, Singapore.
  • 3. School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
  • 4. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, United States.
  • 5. Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Centre, Singapore 138602, Singapore.
  • 6. Department of Chemistry and Biochemistry, Montana State University, 103 Chemistry and Biochemistry, Bozeman, Montana 59717, United States.
  • 7. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
  • 8. Division of Pathogen Biology, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Hirschengraben 84, Zurich 8001, Switzerland.
  • 9. Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore 637551, Singapore.
  • 10. National Centre for Infectious Diseases, Singapore 308442, Singapore.
  • 11. ASTAR Infectious Diseases Laboratories (ASTAR ID Laboratories), Agency for Science, Technology and Research (ASTAR), Singapore 138648, Singapore.
PMID: 41528067 DOI: 10.1021/acs.jmedchem.5c01616
Abstract

The Mycobacterium tuberculosis cytochrome bcc:aa3 (cyt-bcc:aa3) oxidase is a validated drug target for tuberculosis treatment. In addition to telacebec (Q203), a clinical-stage drug candidate, several preclinical cyt-bcc:aa3 inhibitors have been reported. However, the bactericidal potency of cyt-bcc:aa3 inhibitors is limited by cytochrome bd oxidase (cyt-bd), an alternative terminal oxidase. We developed a high-throughput whole-mycobacteria assay to identify new cyt-bd inhibitors. Screening 115,398 small molecules identified several new chemical series, including a pyrazolo-quinazoline amine series. Chemical optimization yielded the potent derivative ETX1975-3, which, in combination with Q203, is bactericidal against M. tuberculosis, retains activity against a panel of M/XDR M. tuberculosis clinical isolates, and also shows efficacy against nontuberculous mycobacteria (NTM). Mode of action studies validated the cyt-bd target as the molecular target. While further chemical optimization is required, favorable microbiological, ADMET, and in vivo potency of ETX1975-3 makes it a promising preclinical candidate for tuberculosis and NTM infections.

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