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

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

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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