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

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 50 = 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 50 = 0.23 μM) versus the parent F0045(S) (EC 50 = 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.