Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent.

Abstract

Multidrug-resistant pulmonary tuberculosis (MDR-TB) is a major health problem worldwide. The treatment for MDR-TB requires medications for a long duration (up to 20-24 months) with second-line drugs resulting in unfavorable outcomes. Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Delamanid and pretomanid are two nitroimidazoles approved by the regulatory agencies for MDR-TB treatment. However, both agents possess unsatisfactory absorption and QTc prolongation. In our search for a safer nitroimidazole, we discovered JBD0131 (2). It exhibited excellent anti-mycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, reduced QT prolongation potential of delamanid. JBD0131 is currently in clinical development in China for pulmonary tuberculosis (CTR20202308).

• Authors: Wei Luo, Zhigang Huang, Deming Xu, Meng Yang, Yusong Zhu, Liang Shen, Shuhui Chen, Xin Tao, Wang Bin, Yinghu Hu, Scott G Franzblau, Ning Jiang, Yuquan Wei, Xiawei Wei, Charles Z Ding
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 72 Pg. 128871 (09 15 2022) ISSN: 1464-3405 [Electronic] England
• PMID: 35777718 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Antitubercular Agents
• Nitroimidazoles
• Oxazoles

Topics

• Antitubercular Agents (pharmacology, therapeutic use)
• Humans
• Mycobacterium tuberculosis
• Nitroimidazoles (pharmacology, therapeutic use)
• Oxazoles (pharmacology, therapeutic use)
• Tuberculosis, Multidrug-Resistant (drug therapy)
• Tuberculosis, Pulmonary (drug therapy, microbiology)