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

• Published in: Bioorganic & medicinal chemistry letters Vol. 72; p. 128871
• Main Authors: Luo, Wei, Huang, Zhigang, Xu, Deming, Yang, Meng, Zhu, Yusong, Shen, Liang, Chen, Shuhui, Tao, Xin, Bin, Wang, Hu, Yinghu, Franzblau, Scott G., Jiang, Ning, Wei, Yuquan, Wei, Xiawei, Ding, Charles Z.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.09.2022; Elsevier
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Delamanid; JBD0131; Life Sciences & Biomedicine; MDR-TB; Mycobacterium tuberculosis; Nitroimidazole; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; WXWH0131; MDR-TB; JBD0131; Mycobacterium tuberculosis; WXWH0131; Delamanid; Nitroimidazole; DRUG; ALLIANCE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.128871

[Display omitted] 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).