2. Academic Validation
  3. Synthesis and anti-influenza virus activity of substituted dibenzoxepine-based baloxavir derivatives

Synthesis and anti-influenza virus activity of substituted dibenzoxepine-based baloxavir derivatives

  • Eur J Med Chem. 2024 Sep 28:280:116922. doi: 10.1016/j.ejmech.2024.116922.
Yongzhi Chen 1,  Qifan Zhou 2,  Fan Pan 1,  Binhao Rong 3,  Renwei Xiao 1,  Yuanmei Wen 1,  Jingyuan Song 4,  Zhengchao Tu 5,  Shuwen Liu 6,  Yingjun Li 7,  Xumu Zhang 8
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China.
  • 2 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China. Electronic address: zhouqf@sustech.edu.cn.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 4 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China; State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510180, China.
  • 5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China.
  • 6 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou, 510515, China. Electronic address: liusw@smu.edu.cn.
  • 7 State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510180, China. Electronic address: liyjun@gzhmu.edu.cn.
  • 8 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China. Electronic address: zhangxm@sustech.edu.cn.
PMID: 39388905 DOI: 10.1016/j.ejmech.2024.116922
Abstract

Seasonal influenza poses a significant threat to global public health, driving the need for effective anti-influenza agents. The PA protein, which captures the pre-mRNA cap structure, is crucial for the replication of the Influenza Virus and serves as an important target for developing such agents. Baloxavir, a PA inhibitor, has shown excellent activity against influenza A and B viruses. In this study, its structure was optimized using bioisosteric replacement to develop novel dibenzoxepine-based derivatives for combating influenza. As the lead compounds, ATV03 (EC50 = 0.78 ± 0.10 nM, SI > 64103) and ATV07 (EC50 = 0.78 ± 0.01 nM, SI = 31603) demonstrated excellent anti-influenza A (H3N2) activity and SI, and possessed favorable anti-influenza B activity, with 2.02 ± 0.40 nM and 2.32 ± 0.29 nM of EC50 respectively. They showed improved bioavailability and metabolic stability. Mechanism studies revealed that ATV03 and ATV07 both possessed significant activity in inhibiting PA and RdRp as well as disturbing NP. Consequently, ATV03 was selected for further investigation in the fight against seasonal and pandemic influenza due to its superior bioavailability, metabolic stability, and efficacy against multiple influenza A viruses.

Keywords

Anti-influenza activity; Dibenzoxepine; PA inhibitor; RNA-Dependent RNA polymerase; Structural optimization.

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