2. Academic Validation
  3. Identification of benzothiazinones containing 2-benzyl-2,7-diazaspiro[3.5]nonane moieties as new antitubercular agents

Identification of benzothiazinones containing 2-benzyl-2,7-diazaspiro[3.5]nonane moieties as new antitubercular agents

  • Eur J Med Chem. 2020 Aug 15;200:112409. doi: 10.1016/j.ejmech.2020.112409.
Apeng Wang 1,  Chao Ma 1,  Yun Chai 2,  Xiujun Liu 1,  Kai Lv 1,  Lei Fu 3,  Bin Wang 3,  Xuedong Jia 4,  Mingliang Liu 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 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Institute of Medical Research, Northwestern Polytechnical University, 127 West Youyi Road, Xi'an, Shanxi, 710072, China.
  • 3 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.
  • 4 The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 5 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lmllyx@126.com.
  • 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: luyu4876@hotmail.com.
PMID: 32460114 DOI: 10.1016/j.ejmech.2020.112409
Abstract

A series of new benzothiazinone derivatives containing a symmetric 2-benzyl-2,7-diazaspiro[3.5]nonane moiety, based on the structure of LK02 discovered in our lab, were designed and synthesized. With one exception 3, all of them show excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016 μg/mL). Compound 2d with a methyl group at the benzylic carbon, was identified to have good safety and significant efficacy in an acute mouse model of TB, as well as better PK profiles than PBTZ169.

Keywords

2,7-diazaspiro[3.5]nonane; Antimycobacterial activity; Benzothiazinones; Synthesis.

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