Discovery of a spirocyclic influenza RNA-dependent RNA polymerase inhibitor

  • Bioorg Chem. 2025 Nov:166:109109. doi: 10.1016/j.bioorg.2025.109109.
Jianxun He  1 ,  Zhaoxing Chu  2 ,  Qinlong Xu  2 ,  Yi Zou  3 ,  Gaofeng Lin  2 ,  Jiajia Mo  1 ,  Li Shao  4 ,  Yan Zhao  2 ,  Jiaming Li  5 ,  Wenfeng Ye  2 ,  Tao Fang  2 ,  Qihua Zhu  6 ,  Guangwei He  7 ,  Yungen Xu  8
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • 2. Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • 3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 4. Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 5. College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 6. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
  • 7. Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China. Electronic address: [email protected].
  • 8. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: [email protected].
PMID: 41172783 DOI: 10.1016/j.bioorg.2025.109109
Abstract

The cap-dependent Endonuclease (CEN) inhibitor baloxavir marboxil (1) was approved by the FDA as a significant advancement in influenza treatment in nearly two decades. By expanding the tricyclic scaffold of baloxavir and introducing a spirocyclic architecture, a range of innovative compounds were designed and synthesized. Through iterative cycles of compound design and structure-activity relationship (SAR) analysis, guided by the cytopathic effect (CPE) assay, influenza polymerase inhibitory activity assay and molecular docking results, we hypothesized that the newly designed spirocyclic compounds could form a novel hydrogen-bonding interaction with the Tyr24 amino acid residue within the receptor binding pocket. Lead compound (S,S)-5a exhibited potent anti-influenza virus activity (EC50 = 3.76 nM), relatively low cytotoxicity (CC50 = 29.91 μM), and favorable liver microsomal stability. Moreover, both (S,S)-5a and its prodrug 6 effectively suppressed viral replication in a mouse model infected with A/WSN/33, demonstrating promising efficacy profiles. Both compound (S,S)-5a and its unique binding mode with the receptor warrant further investigation.

Keywords
CEN inhibitor; Influenza; Tyr24 amino acid residue; spirocyclic structure.
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