2. Academic Validation
  3. Design and synthesis of Thieno[3, 2-b]pyridinone derivatives exhibiting potent activities against Mycobacterium tuberculosis in vivo by targeting Enoyl-ACP reductase

Design and synthesis of Thieno[3, 2-b]pyridinone derivatives exhibiting potent activities against Mycobacterium tuberculosis in vivo by targeting Enoyl-ACP reductase

  • Eur J Med Chem. 2024 Aug 31:279:116806. doi: 10.1016/j.ejmech.2024.116806.
Lihong Liang 1,  Zhiyong Liu 2,  Jie Chen 3,  Qin Zha 1,  Yihuan Zhou 1,  Jun Li 4,  Yangbo Hu 5,  Xinwen Chen 6,  Tianyu Zhang 7,  Niuniu Zhang 8
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China.
  • 2 State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • 3 Jiaxing University Affiliated Hospital, The First Hospital of Jiaxing, Jiaxing, 314001, China.
  • 4 Shanghai Institute for Advanced Immunochemical Studies and School of Life Science and Technology, Shanghai Tech University, Shanghai, 201210, China.
  • 5 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
  • 6 Guangzhou National Laboratory, Guangzhou, 510005, China.
  • 7 State Key Laboratory of Respiratory Disease, Guangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious Diseases, China-New Zealand Joint Laboratory on Biomedicine and Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China; Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, 510530, China; Guangzhou National Laboratory, Guangzhou, 510005, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: zhang_tianyu@gibh.ac.cn.
  • 8 Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin, 541199, China. Electronic address: zhangniuniuu@yeah.net.
PMID: 39276583 DOI: 10.1016/j.ejmech.2024.116806
Abstract

In this study, a series of novel thieno [3, 2-b]pyridinone derivatives were designed and synthesized using a scaffold hopping strategy. Six compounds showed potent anti-mycobacterial activity (minimum inhibitory concentration (MIC) ≤ 1 μg/mL) against Mycobacterium tuberculosis (Mtb) UAlRa. Compound 6c displayed good activity against Mtb UAlRv (MIC = 0.5-1 μg/mL). Compounds 6c and 6i also showed activity against Mtb UAlRa in macrophages and exhibited low cytotoxicity against LO-2 cells. The selected compounds displayed a narrow Antibacterial spectrum, with no activity against representative Gram-positive, Gram-negative bacteria, as well as fungi. Furthermore, compound 6c demonstrated favorable oral pharmacokinetic properties with a T1/2 value of 47.99 h and exhibited good in vivo activity in an acute mouse model of tuberculosis (TB). The target of compound 6c was identified as a NADH-dependent enoyl-acyl carrier protein reductase (InhA) by genome Sequencing of spontaneously compound 6c-resistant Mtb mutants, indicating that compound 6c may not require activation and can directly target InhA. In vitro antimicrobial assays against a recombinant M. smegmatis overexpressing the Mtb-InhA, along with InhA inhibition assays, confirmed that InhA is the target of thieno [3, 2-b]pyridinone derivatives. Overall, this study identified thieno [3, 2-b]pyridinone scaffold as a novel chemotype that is promising for the development of anti-TB agents.

Keywords

Anti-Tuberculosis activity; InhA; Scaffold hopping; Thieno[3, 2-b]pyridinone.

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