tetano
Editor, Senior Moderator
J Med Chem
. 2026 Mar 25.
doi: 10.1021/acs.jmedchem.5c02937. Online ahead of print.
Discovery and Optimization of Benzenesulfonamides as Potent Influenza A Virus Hemagglutinin Inhibitors
Huijuan Song[SUP] 1 2 [/SUP], Apeng Wang[SUP] 1 [/SUP], Shiyong Fan[SUP] 3 [/SUP], Sheng Zhou[SUP] 4 [/SUP], Hongyi Yan[SUP] 5 [/SUP], Ge Yang[SUP] 1 [/SUP], Jiaqi Gong[SUP] 1 [/SUP], Yuhui Zhang[SUP] 5 [/SUP], Kai Liu[SUP] 5 [/SUP], Xiaohui Xie[SUP] 5 [/SUP], Mingliang Liu[SUP] 1 [/SUP], Haiyan Yan[SUP] 1 [/SUP], Kai Zhang[SUP] 4 [/SUP], Yuhuan Li[SUP] 1 [/SUP], Kai Lv[SUP] 1 [/SUP]
Affiliations
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 (EC[SUB]50[/SUB] = 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 (EC[SUB]50[/SUB] = 0.23 μM) versus the parent F0045(S) (EC[SUB]50[/SUB] = 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.
. 2026 Mar 25.
doi: 10.1021/acs.jmedchem.5c02937. Online ahead of print.
Discovery and Optimization of Benzenesulfonamides as Potent Influenza A Virus Hemagglutinin Inhibitors
Huijuan Song[SUP] 1 2 [/SUP], Apeng Wang[SUP] 1 [/SUP], Shiyong Fan[SUP] 3 [/SUP], Sheng Zhou[SUP] 4 [/SUP], Hongyi Yan[SUP] 5 [/SUP], Ge Yang[SUP] 1 [/SUP], Jiaqi Gong[SUP] 1 [/SUP], Yuhui Zhang[SUP] 5 [/SUP], Kai Liu[SUP] 5 [/SUP], Xiaohui Xie[SUP] 5 [/SUP], Mingliang Liu[SUP] 1 [/SUP], Haiyan Yan[SUP] 1 [/SUP], Kai Zhang[SUP] 4 [/SUP], Yuhuan Li[SUP] 1 [/SUP], Kai Lv[SUP] 1 [/SUP]
Affiliations
- PMID: 41879742
- DOI: 10.1021/acs.jmedchem.5c02937
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 (EC[SUB]50[/SUB] = 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 (EC[SUB]50[/SUB] = 0.23 μM) versus the parent F0045(S) (EC[SUB]50[/SUB] = 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.