Rhodanine-Inspired Development of Dual-Action Mycobacterium tuberculosis Protein Tyrosine Phosphatase B Inhibitors

  • J Med Chem. 2026 May 28;69(10):12223-12239. doi: 10.1021/acs.jmedchem.6c00103.
Haofan Shao  1  2 ,  Xiaoyu Wu  3 ,  Shihao Cheng  4 ,  Bin Wang  5 ,  Xi Chen  5 ,  Yixuan Zheng  4 ,  Zhenfa Yang  1  2 ,  Jiang Li  4 ,  Fei Ye  4 ,  Yu Lu  5 ,  Haihong Huang  1  2 ,  Zhenhuang Ge  3 ,  Dongfeng Zhang  1  2
Affiliations
  • 1. State Key Laboratory of Respiratory Health and Multimorbidity, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2. 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, China.
  • 3. School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510275, China.
  • 4. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 5. Beijing Key Laboratory for Key Technologies in Tuberculosis Prevention and Control, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China.
PMID: 42090543 DOI: 10.1021/acs.jmedchem.6c00103
Abstract

We developed a pharmacophore fusion strategy to design dual-action Mycobacterium tuberculosis protein tyrosine Phosphatase B (MptpB) inhibitors. This involved integrating rhodanine-3-acetic acid with the nitroimidazooxazine/oxazole core of antitubercular nitroimidazoles. The resulting compounds showed potent MptpB inhibition and direct antituberculosis activity. Docking studies indicated a conserved binding mode, with the rhodanine moiety in the P1 pocket and the nitroimidazole core in the P2 pocket. Compound 4 was most promising, exhibiting strong MptpB inhibition (IC50: 0.19 μM), good antituberculosis efficacy (MIC: 1.94 μg/mL), and high selectivity over human PTP1B (345-fold). It also demonstrated excellent metabolic stability, good permeability, acceptable bioavailability in mice, low cytotoxicity, and outperformed Rifampicin and Pretomanid in a macrophage Infection model. Mechanistic studies showed that it reversed MptpB-mediated suppression of the macrophage MAPK pathway. This work validates the fusion strategy and identifies a promising lead targeting MptpB for further development.

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