2. Academic Validation
  3. Discovery of furo[2,3-b]isoquinoline derivatives as novel Pks13 inhibitors with reduced hERG inhibition

Discovery of furo[2,3-b]isoquinoline derivatives as novel Pks13 inhibitors with reduced hERG inhibition

  • Bioorg Med Chem Lett. 2026 May:134:130561. doi: 10.1016/j.bmcl.2026.130561.
Jiangfeng Tian 1,  Renyu Zhang 2,  Zhiyang Xing 3,  Yuanyuan Liu 1,  Weijie Lin 2,  Xupeng Huang 4,  Zihe Rao 5,  Wei Peng 6,  Yuying Fang 7
Affiliations

Affiliations

  • 1 School of Chemistry and Chemical Engineering, University of South China, Hengyang 421001, China; Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China.
  • 2 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China.
  • 3 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China.
  • 4 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China. Electronic address: [email protected].
  • 5 Laboratory of Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing, China. Electronic address: [email protected].
  • 6 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China; Guangzhou Medical University, Guangzhou, 511436, China; Department of Infectious Diseases, The Key Laboratory of Advanced Interdisciplinary Studies, The First Affiliated Hospital, Guangzhou Medical University, State Key Laboratory of Respiratory Disease, Guangzhou 511436, China. Electronic address: [email protected].
  • 7 Innovative Center for Pathogen Research, Guangzhou National Laboratory, Guangzhou, 510005, China. Electronic address: [email protected].
PMID: 41605335 DOI: 10.1016/j.bmcl.2026.130561
Abstract

Pks13 is a promising target for tuberculosis (TB) treatment, offering a new pathway for anti-TB drug development. Although benzofuran derivatives such as TAM16 have demonstrated significant efficacy in vitro and in vivo, their development was discontinued due to concerns about hERG inhibition. Herein, we designed and synthesized a series of novel furo[2,3-b]isoquinoline derivatives using ring fusion and basicity-reduction strategies. Through SAR studies, compound B23 was identified as a potent Pks13 inhibitor (IC50 = 1.12 μM) with significantly reduced hERG inhibition (IC50 > 10 μM). The markedly improved hERG selectivity not only validates our structural strategy for mitigating cardiotoxicity risks, but also provides a solid foundation for further development of Pks13-TE inhibitors that combine potent anti-TB activity with an improved safety profile.

Keywords

Pks13-TE; Tuberculosis; hERG.

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