Discovery of Potent Benzoselenazinone-Based DprE1 Inhibitors: A Novel Selenium-Containing Scaffold with Superior Anti-TB Activity and Pharmacokinetic Properties

  • J Med Chem. 2026 May 14;69(9):10579-10593. doi: 10.1021/acs.jmedchem.5c03770.
Yang Liu  1 ,  Xiuli Xu  1 ,  Chengxia Mao  2 ,  Bin Wang  3 ,  Mario Cocorullo  4 ,  Andrea Tresoldi  5 ,  Matteo Mori  5 ,  Baolian Wang  2 ,  Yu Lu  3 ,  Haihong Huang  1 ,  Laurent R Chiarelli  4 ,  Peng Li  1
Affiliations
  • 1. State Key Laboratory of Respiratory Health and Multimorbidity, Beijing Key Laboratory for Key Technologies in Tuberculosis Prevention and Control, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China.
  • 2. Department of Drug Metabolism, Beijing Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P. R. China.
  • 3. Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, P. R. China.
  • 4. Department of Biology and Biotechnology "Lazzaro Spallanzani", University of Pavia, Pavia 27100, Italy.
  • 5. Department of Pharmaceutical Sciences, University of Milan, Milan 20133, Italy.
PMID: 41996283 DOI: 10.1021/acs.jmedchem.5c03770
Abstract

Tuberculosis remains one of the world's most devastating infectious diseases. Targeting the essential cell wall enzyme, DprE1 has emerged as a promising therapeutic strategy. In this study, we report the discovery of a novel selenium-containing scaffold, benzoselenazinones (BSZs), which was designed through selenium-for-sulfur replacement in benzothiazinones (BTZs) to combine DprE1 inhibition with the pharmacological benefits of organoselenium compounds. Most BSZ derivatives exhibited exceptional anti-TB activity (MICs < 0.03 μM), low cytotoxicity (Vero IC50s > 100 μM), and potent DprE1 inhibition (IC50s < 0.1 μM). Moreover, compound 11c demonstrated superior oral bioavailability (F % = 31.9%) compared to the representative PBTZ169 of BTZs in CD-1 mice, positioning it as a promising preclinical candidate. This study highlights the potential of selenium-based bioisosteres in anti-TB drug discovery and offers a novel benzoselenazinone scaffold with enhanced efficacy and safety for further development.

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