2. Academic Validation
  3. Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety

Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety

  • Eur J Med Chem. 2023 Oct 5;258:115545. doi: 10.1016/j.ejmech.2023.115545.
Apeng Wang 1,  Na Du 1,  Huijuan Song 1,  Yuehao Zhang 2,  Xijun Zhong 1,  Jizhou Wu 1,  Tiezheng Xue 2,  Mingliang Liu 3,  Bin Wang 4,  Kai Lv 5,  Yu Lu 6
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 Hebei Medical University, Shijiazhuang, 050017, China.
  • 3 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital College of Pharmacy, Medical University, Beijing, 100149, China.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 6 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital College of Pharmacy, Medical University, Beijing, 100149, China. Electronic address: [email protected].
PMID: 37300914 DOI: 10.1016/j.ejmech.2023.115545
Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N-(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H37Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD50 > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery.

Keywords

Acute toxicity; Antitubercular activity; Benzothiazinones; N-(amino)piperazine; Synthesis.

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