Design, Synthesis, and Antitubercular Activity Evaluation of Novel Nitroimidazole Derivatives

  • J Med Chem. 2026 Jun 25;69(12):14213-14235. doi: 10.1021/acs.jmedchem.5c03631.
Guoquan Wan  1  2 ,  Yan Chen  1 ,  Xiaorui Zhang  3 ,  Qifan Tang  1 ,  Qiangsheng Zhang  4 ,  Shuyan Zhou  1 ,  Wentao Li  1 ,  Jumei Zeng  3 ,  Chao Gao  5 ,  Luoting Yu  1
Affiliations
  • 1. State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2. Department of Pharmacy, the Third Affiliated Hospital (the First Hospital of Nanchang), Jiangxi Medical College, Nanchang University, Nanchang 330008, China.
  • 3. West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
  • 4. School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
  • 5. Laboratory of Human Diseases and Immunotherapies, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
PMID: 42262108 DOI: 10.1021/acs.jmedchem.5c03631
Abstract

The development of novel antitubercular agents represents a critical strategy against drug-resistant tuberculosis (TB). In this study, we designed and synthesized a series of novel nitroimidazole derivatives from Delemanid by introducing an aliphatic spirocyclic moiety. Most compounds demonstrated potent in vitro antitubercular activity with negligible cytotoxicity. Compound TB-212 exhibited superior activity against Mtb H37Ra over Delamanid (MIC values: 0.2 vs 1.0 ng/mL), and maintained robust efficacy against clinical drug-resistant strains. Importantly, TB-212 displayed significantly improved solubility, higher permeability in Caco-2 cell and a lower risk of cardiotoxicity. PK studies revealed that TB-212 absorbed rapidly following oral administration, with drug exposure exhibiting a favorable linear dose-proportional manner, distinct from the nonlinear PK profile of Delamanid. In a mouse model of TB, TB-212 outperformed Delamanid in terms of in vivo therapeutic efficacy. Collectively, these findings highlight the promising therapeutic potential of TB-212, particularly for the treatment of drug-resistant TB.

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