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

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

  • Bioorg Med Chem Lett. 2022 Sep 15:72:128871. doi: 10.1016/j.bmcl.2022.128871.
Wei Luo 1,  Zhigang Huang 1,  Deming Xu 2,  Meng Yang 2,  Yusong Zhu 2,  Liang Shen 2,  Shuhui Chen 2,  Xin Tao 3,  Wang Bin 4,  Yinghu Hu 1,  Scott G Franzblau 5,  Ning Jiang 6,  Yuquan Wei 7,  Xiawei Wei 8,  Charles Z Ding 9
Affiliations

Affiliations

  • 1 WuXi AppTec, 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China.
  • 2 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
  • 3 Changzhou Yinsheng Pharmacy Co., Ltd., Weitang Chemical Industry Zone, Changzhou 213000, China.
  • 4 Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis, and Thoracic Tumor Research Institute, Beijing, China.
  • 5 Institute for Tuberculosis Research, College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, United States.
  • 6 Jumbo Drug Bank Co., Ltd., No.18, Section 2, Bio-city Middle Road, High-tech Zone, Chengdu, Sichuan 610000, China.
  • 7 State Key Lab of Biotherapy, Sichuan University, No 17, The Third Renmin South Road, Chengdu, Sichuan 610041, China.
  • 8 Jumbo Drug Bank Co., Ltd., No.18, Section 2, Bio-city Middle Road, High-tech Zone, Chengdu, Sichuan 610000, China. Electronic address: [email protected].
  • 9 WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China. Electronic address: [email protected].
PMID: 35777718 DOI: 10.1016/j.bmcl.2022.128871
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).

Keywords

Delamanid; JBD0131; MDR-TB; Mycobacterium tuberculosis; Nitroimidazole; WXWH0131.

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