2. Academic Validation
  3. Identification of benzothiazinones containing an oxime functional moiety as new anti-tuberculosis agents

Identification of benzothiazinones containing an oxime functional moiety as new anti-tuberculosis agents

  • Eur J Med Chem. 2019 Nov 1:181:111595. doi: 10.1016/j.ejmech.2019.111595.
Apeng Wang 1,  Kai Lv 1,  Zeyu Tao 1,  Jian Gu 2,  Lei Fu 3,  Mingliang Liu 4,  Baojie Wan 5,  Scott G Franzblau 5,  Chao Ma 1,  Xican Ma 6,  Bing Han 6,  Aoyu Wang 7,  Shijie Xu 1,  Yu Lu 8
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 2 College of Pharmacy, Southwest Minzu University, Chengdu, 610041, 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 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lmllyx@126.com.
  • 5 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois, Chicago, IL, 60612, USA.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; College of Pharmacy, Southwest Minzu University, Chengdu, 610041, China.
  • 7 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Hebei Medical University, Shijiazhuang, 050017, China.
  • 8 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: 31408806 DOI: 10.1016/j.ejmech.2019.111595
Abstract

A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037 μg/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.

Keywords

Antimycobacterial activity; Benzothiazinones; Oximes; Synthesis.

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