Design, synthesis and antimycobacterial activity of new benzothiazinones inspired by rifampicin/rifapentine

  • Bioorg Chem. 2020 Sep;102:104135. doi: 10.1016/j.bioorg.2020.104135.
Apeng Wang  1 ,  Yu Lu  2 ,  Kai Lv  1 ,  Chao Ma  1 ,  Shijie Xu  1 ,  Bin Wang  2 ,  Aoyu Wang  3 ,  Guimin Xia  4 ,  Mingliang Liu  5
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2. 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.
  • 3. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Hebei Medical University, Shijiazhuang 050017, China.
  • 4. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
  • 5. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
PMID: 32736151 DOI: 10.1016/j.bioorg.2020.104135
Abstract

A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 μM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Keywords
Antimycobacterial activity; Benzothiazinones; N-((methylene)amino)piperazine; Synthesis.
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