Discovery of Fluorine-Containing Benzoxazinyl-oxazolidinones for the Treatment of Multidrug Resistant Tuberculosis

  • ACS Med Chem Lett. 2017 Apr 12;8(5):533-537. doi: 10.1021/acsmedchemlett.7b00068.
Hongyi Zhao  1  2 ,  Yu Lu  3 ,  Li Sheng  1 ,  Zishuo Yuan  1 ,  Bin Wang  3 ,  Weiping Wang  1 ,  Yan Li  1 ,  Chen Ma  1 ,  Xiaoliang Wang  1 ,  Dongfeng Zhang  1  2 ,  Haihong Huang  1  2
Affiliations
  • 1. State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.
  • 2. Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.
  • 3. Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China.
PMID: 28523106 DOI: 10.1021/acsmedchemlett.7b00068
Abstract

A novel series of fluorine-containing benzoxazinyl-oxazolidinones were designed and synthesized as antidrug-resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound 21 exhibited not only outstanding in vitro activity with a MIC value of 0.25-0.50 μg/mL against drug-susceptible H37Rv strain and two clinically isolated drug-resistant Mycobacterium tuberculosis strains, but also acceptable in vitro ADME/T properties. Moreover, this compound displayed excellent mouse pharmacokinetic profiles with an oral bioavailability of 102% and a longer elimination half-life of 4.22 h, thereby supporting further optimization and development of this promising lead series.

Keywords
Antitubercular agents; drug-resistant tuberculosis (DR-TB); fluoro-benzoxazinyl-oxazolidinones; structure−activity relationships.