2. Academic Validation
  3. Discovery and Optimization of Benzenesulfonamides as Potent Influenza A Virus Hemagglutinin Inhibitors

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

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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