2. Academic Validation
  3. Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

  • Eur J Med Chem. 2024 Sep 3:279:116829. doi: 10.1016/j.ejmech.2024.116829.
Xijun Zhong 1,  Jizhou Wu 1,  Na Du 1,  Sheng Zhou 2,  Chao Ma 3,  Tiezheng Xue 2,  Meng Wei 1,  Jiaqi Gong 1,  Bin Wang 4,  Mingliang Liu 1,  Apeng Wang 5,  Kai Lv 6,  Yu Lu 7
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; MindRank AI Ltd., Hangzhou, 310000, China.
  • 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: wangapengbuct@126.com.
  • 6 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: lvkailk@hotmail.com.
  • 7 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: 39243457 DOI: 10.1016/j.ejmech.2024.116829
Abstract

Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC: <0.029-0.095 μM), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.

Keywords

Antimycobacterial activity; Nitrobenzothiazinones; Synthesis; Water solubility.

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