Discovery and Optimization of Benzenesulfonamides as Potent Influenza A Virus Hemagglutinin Inhibitors

  • J Med Chem. 2026 Apr 9;69(7):7732-7755. doi: 10.1021/acs.jmedchem.5c02937.
Huijuan Song  1  2 ,  Apeng Wang  1 ,  Shiyong Fan  3 ,  Sheng Zhou  4 ,  Hongyi Yan  5 ,  Ge Yang  1 ,  Jiaqi Gong  1 ,  Yuhui Zhang  5 ,  Kai Liu  5 ,  Xiaohui Xie  5 ,  Mingliang Liu  1 ,  Haiyan Yan  1 ,  Kai Zhang  4 ,  Yuhuan Li  1 ,  Kai Lv  1
Affiliations
  • 1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 2. Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
  • 3. Academy of Military Medical Sciences, Beijing 100850, China.
  • 4. Department of Medicinal Chemistry, Hebei Medical University, Shijiazhuang 050017, China.
  • 5. Shijiazhuang Keren Pharmaceutical Technology Co. Ltd., Shijiazhuang 052500, China.
PMID: 41879742 DOI: 10.1021/acs.jmedchem.5c02937
Abstract

Influenza remains a significant global health burden, highlighting the urgent need for Antiviral agents with novel mechanisms of action. Through structure-based design, we introduced a sulfonyl group as a carbonyl bioisostere into the F0045(S) scaffold, yielding SHJ-027 with over 2-fold improved potency (EC50 = 0.56 μM). A systematic structure-activity relationship (SAR) study of this sulfonyl chemotype (>80 analogs) was conducted, yielding potent inhibitors with significantly enhanced pharmacological properties. The lead compound (S)-63 demonstrated over 10-fold enhanced potency against an oseltamivir-resistant strain of H1N1 (EC50 = 0.23 μM) versus the parent F0045(S) (EC50 = 2.94 μM). In a lethal influenza mouse model, preferred compounds (S)-63 and 27 achieved 20-30% survival, while F0045(S) provided 0% protection, establishing clear in vivo efficacy improvement. This study establishes a novel sulfonyl-containing chemotype for HA inhibition, providing a distinct scaffold for the development of next-generation influenza therapeutics.

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