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Discovery and Optimization of Benzenesulfonamides as Potent Influenza A Virus Hemagglutinin Inhibitors
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DOI：10.1021/acs.jmedchem.5c02937.png)
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Abstract
En 中文
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.
Keywords:
Antimicrobial agents
Inhibitors
Lipids
Nuclear magnetic resonance spectroscopy
Viruses
Journal
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6.8
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2.7W
Citations:
9.4W
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Cited Papers