Abstract
A high-throughput, cell-based screen was used to identify chemotypes as inhibitors for human respiratory syncytial virus (hRSV). Optimization of a sulfonylpyrrolidine scaffold resulted in compound 5o that inhibited a virus-induced cytopathic effect in the entry stage of infection (EC₅₀ = 2.3 ± 0.8 μM) with marginal cytotoxicity (CC₅₀ = 30.9 ± 1.1 μM) and reduced viral titer by 100-fold. Compared to ribavirin, sulfonylpyrrolidine 5o demonstrated an improved in vitro potency and selectivity index.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cytopathogenic Effect, Viral / drug effects
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High-Throughput Screening Assays
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Humans
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Quinolines / chemical synthesis*
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Quinolines / chemistry
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Quinolines / pharmacology
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Respiratory Syncytial Viruses / drug effects*
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Respiratory Syncytial Viruses / physiology
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Ribavirin / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Sulfones / chemical synthesis*
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Sulfones / chemistry
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Sulfones / pharmacology
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Viral Load / drug effects
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Virus Internalization / drug effects
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Virus Replication / drug effects
Substances
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Antiviral Agents
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N-(2,5-dimethylphenyl)-1-(quinolin-8-ylsulfonyl)pyrrolidine-2-carboxamide
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Pyrrolidines
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Quinolines
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Sulfonamides
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Sulfones
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Ribavirin