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 (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.